Examining the Neural and Behavioral Impact of Accelerated Intermittent Theta Burst Stimulation in People with Opioid Use Disorder Who Smoke Tobacco Cigarettes: A Pilot Study
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Examining the Neural and Behavioral Impact of Accelerated Intermittent Theta Burst Stimulation in People with Opioid Use Disorder Who Smoke Tobacco Cigarettes: A Pilot Study
Novel therapies are needed to improve smoking cessation outcomes in people with opioid use disorder (OUD), as they are far more likely to smoke cigarettes (70–90%) compared to the general population (11.6%) and demonstrate a poorer response to smoking cessation interventions.
Methods:
This pilot study, intended to be a hypothesis-generating mechanistic investigation, is the first to explore the impact of a single day (four sessions) of accelerated intermittent theta burst stimulation (iTBS) (1800 pulses/session) versus sham iTBS applied to the left dorsolateral prefrontal cortex (L-dlPFC) in people with OUD who smoke tobacco cigarettes (n = 8 received iTBS, n = 7 received sham iTBS). Resting-state functional connectivity was acquired at baseline and after the fourth session. Attentional bias for cigarette and opioid cues, and craving assessments, were completed at baseline, and after the first and fourth sessions.
Results:
Connectivity between the L-dlPFC seed and a cluster comprising the left anterior supramarginal gyrus showed a significant group × time interaction, with planned comparisons showing a greater increase at follow-up in the iTBS compared with sham iTBS group (t12 = 6.37, β = 0.40, p < 0.001). Cigarette cue attentional bias showed a significant group × session interaction (t80 = 2.34, p = 0.02), with planned comparisons showing a decrease after iTBS and an increase following sham iTBS. No effect of iTBS was observed for opioid cue attentional bias. Cigarette craving decreased in both iTBS and sham groups but did not show a significant group × session interaction.
Conclusions:
These results are promising but should be interpreted with caution, given the limited sample size, which precluded analyses adjusting for sex or medications for OUD. This pilot study aims to identify neural and behavioral targets for future studies of accelerated iTBS in people with OUD who smoke cigarettes. Future trials could examine the effects of increased doses of iTBS (e.g., more days of accelerated iTBS) to identify dosing to promote smoking cessation among individuals with OUD effectively.
Impact Statement
Accelerated intermittent theta burst stimulation has been paradigm-shifting in the treatment of major depressive disorder. Similarly, it could provide a robust and efficient adjunct smoking cessation intervention for people with OUD who smoke cigarettes.
AlkhasliI, SakreidaK, MottaghyFM, et al.Modulation of fronto-striatal functional connectivity using transcranial magnetic stimulation. Front Hum Neurosci2019;13:190; doi: 10.3389/fnhum.2019.00190
2.
AtayaAF, AdamsS, MullingsE, et al.Internal reliability of measures of substance-related cognitive bias. Drug Alcohol Depend2012;121(1–2):148–151; doi: 10.1016/j.drugalcdep.2011.08.023
3.
BeltzAM, BerenbaumSA, WilsonSJ. Sex differences in resting state brain function of cigarette smokers and links to nicotine dependence. Exp Clin Psychopharmacol2015;23(4):247–254; doi: 10.1037/pha0000033
4.
BerridgeKC, RobinsonTE. Liking, wanting, and the incentive-sensitization theory of addiction. Am Psychol2016;71(8):670–679; doi: 10.1037/amp0000059
5.
ChangKY, TikM, Mizutani-TiebelY, et al.Dose-dependent target engagement of a clinical intermittent theta burst stimulation protocol: An interleaved transcranial magnetic stimulation-functional magnetic resonance imaging study in healthy people. Biol Psychiatry Cogn Neurosci Neuroimaging2025;10(8):804–813; doi: 10.1016/j.bpsc.2024.08.009
6.
ChenJ, LiY, WangS, et al.Methadone maintenance treatment alters couplings of default mode and salience networks in individuals with heroin use disorder: A longitudinal self-controlled resting-state fMRI study. Front Psychiatry2023;14:1132407; doi: 10.3389/fpsyt.2023.1132407
7.
ChumbleyJ, WorsleyK, FlandinG, et al.Topological FDR for neuroimaging. Neuroimage2010;49(4):3057–3064; doi: 10.1016/j.neuroimage.2009.10.090
8.
CieslikEC, ZillesK, CaspersS, et al.Is there “one” DLPFC in cognitive action control? Evidence for heterogeneity from co-activation-based parcellation. Cereb Cortex2013;23(11):2677–2689; doi: 10.1093/cercor/bhs256
9.
ColeEJ, PhillipsAL, BentzleyBS, et al.Stanford neuromodulation therapy (SNT): A double-blind randomized controlled trial. Am J Psychiatry2022;179(2):132–141; doi: 10.1176/appi.ajp.2021.20101429
10.
CustodioL, MaloneS, BardoMT, et al.Nicotine and opioid co-dependence: Findings from bench research to clinical trials. Neurosci Biobehav Rev2022;134:104507; doi: 10.1016/j.neubiorev.2021.12.030
11.
DavisJP, EddieD, PrindleJ, et al.Sex differences in factors predicting post-treatment opioid use. Addiction2021;116(8):2116–2126; doi: 10.1111/add.15396
12.
DielerAC, DreslerT, JoachimK, et al.Can intermittent theta burst stimulation as add-on to psychotherapy improve nicotine abstinence? Results from a pilot study. Eur Addict Res2014;20(5):248–253; doi: 10.1159/000357941
13.
EkhtiariH, KuplickiR, PruthiA, et al.Methamphetamine and opioid cue database (MOCD): Development and validation. Drug Alcohol Depend2020;209:107941; doi: 10.1016/j.drugalcdep.2020.107941
14.
FedotaJR, SteinEA. Resting-state functional connectivity and nicotine addiction: Prospects for biomarker development. Ann N Y Acad Sci2015;1349(1):64–82; doi: 10.1111/nyas.12882
15.
FieldM, ChristiansenP. Commentary on, ‘Internal reliability of measures of substance-related cognitive bias’. Drug Alcohol Depend2012;124(3):189–190; doi: 10.1016/j.drugalcdep.2012.02.009
16.
FoxMD, BucknerRL, WhiteMP, et al.Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry2012;72(7):595–603; doi: 10.1016/j.biopsych.2012.04.028
17.
GongH, HuangY, ZhuX, et al.Impact of combination of intermittent theta burst stimulation and methadone maintenance treatment in individuals with opioid use disorder: A comparative study. Psychiatry Res2023;327:115411; doi: 10.1016/j.psychres.2023.115411
18.
GuydishJ, PassalacquaE, PaganoA, et al.An international systematic review of smoking prevalence in addiction treatment. Addiction2016;111(2):220–230; doi: 10.1111/add.13099
19.
HeathertonTF, KozlowskiLT, FreckerRC, et al.The fagerstrom test for nicotine dependence: A revision of the Fagerstrom Tolerance Questionnaire. Br J Addict1991;86(9):1119–1127; doi: 10.1111/j.1360-0443.1991.tb01879.x
20.
HeishmanSJ, SingletonEG, PickworthWB. Reliability and validity of a short form of the Tobacco Craving Questionnaire. Nicotine Tob Res2008;10(4):643–651; doi: 10.1080/14622200801908174
21.
HigginsST, KurtiAN, RednerR, et al.A literature review on prevalence of gender differences and intersections with other vulnerabilities to tobacco use in the United States, 2004–2014. Prev Med2015;80:89–100; doi: 10.1016/j.ypmed.2015.06.009
22.
IeongHF, YuanZ. Resting-State neuroimaging and neuropsychological findings in opioid use disorder during abstinence: A review. Front Hum Neurosci2017;11:169; doi: 10.3389/fnhum.2017.00169
23.
JordanT, ApostolMR, NomiJ, et al.Unraveling neural complexity: Exploring brain entropy to yield mechanistic insight in neuromodulation therapies for tobacco use disorder. bioRxiv2023:2023.09.12.557465; doi: 10.1101/2023.09.12.557465
24.
KangT, DingX, ZhaoJ, et al.Influence of improved behavioral inhibition on decreased cue-induced craving in heroin use disorder: A preliminary intermittent theta burst stimulation study. J Psychiatr Res2022;152:375–383; doi: 10.1016/j.jpsychires.2022.06.010
25.
LiQ, LiZ, LiW, et al.Disrupted default mode network and basal craving in male heroin-dependent individuals: A resting-state fMRI study. J Clin Psychiatry2016;77(10):e1211–e1217; doi: 10.4088/JCP.15m09965
26.
LiX, DuL, SahlemGL, et al.Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex reduces resting-state insula activity and modulates functional connectivity of the orbitofrontal cortex in cigarette smokers. Drug Alcohol Depend2017;174:98–105; doi: 10.1016/j.drugalcdep.2017.02.002
27.
LichensteinSD, ZakiniaeizY, YipSW, et al.Mechanisms and clinical features of co-occurring opioid and nicotine use. Curr Addict Rep2019;6(2):114–125; doi: 10.1007/s40429-019-00245-3
28.
MacLeanRR, SofuogluM, BredeE, et al.Attentional bias in opioid users: A systematic review and meta-analysis. Drug Alcohol Depend2018;191:270–278; doi: 10.1016/j.drugalcdep.2018.07.012
29.
MannelliP, WuLT, PeindlKS, et al.Smoking and opioid detoxification: Behavioral changes and response to treatment. Nicotine Tob Res2013;15(10):1705–1713; doi: 10.1093/ntr/ntt046
30.
ManoliuA, HauggA, SladkyR, et al.SmoCuDa: A validated smoking cue database to reliably induce craving in tobacco use disorder. Eur Addict Res2021;27(2):107–114; doi: 10.1159/000509758
31.
MasieroM, LucchiariC, MaisonneuveP, et al.The attentional bias in current and former smokers. Front Behav Neurosci2019;13:154; doi: 10.3389/fnbeh.2019.00154
32.
McCalleyDM, LenchDH, DoolittleJD, et al.Determining the optimal pulse number for theta burst induced change in cortical excitability. Sci Rep2021;11(1):8726; doi: 10.1038/s41598-021-87916-2
33.
McClureSM, BickelWK. A dual-systems perspective on addiction: Contributions from neuroimaging and cognitive training. Ann N Y Acad Sci2014;1327:62–78; doi: 10.1111/nyas.12561
34.
McHughRK, FitzmauriceGM, CarrollKM, et al.Assessing craving and its relationship to subsequent prescription opioid use among treatment-seeking prescription opioid dependent patients. Drug Alcohol Depend2014;145:121–126; doi: 10.1016/j.drugalcdep.2014.10.002
35.
MehtaDD, PraechtA, WardHB, et al.A systematic review and meta-analysis of neuromodulation therapies for substance use disorders. Neuropsychopharmacology2024;49(4):649–680; doi: 10.1038/s41386-023-01776-0
36.
MenonV, UddinLQ. Saliency, switching, attention and control: A network model of insula function. Brain Struct Funct2010;214(5–6):655–667; doi: 10.1007/s00429-010-0262-0
37.
MikellidesG, MichaelP, PsaltaL, et al.Accelerated intermittent theta burst stimulation in smoking cessation: Placebo effects equal to active stimulation when using advanced placebo coil technology. Front Psychiatry2022;13:892075; doi: 10.3389/fpsyt.2022.892075
38.
MikellidesG, MichaelP, PsaltaL, et al.Accelerated intermittent theta burst stimulation in smoking cessation: No differences between active and placebo stimulation when using advanced placebo coil technology. A double-blind follow-up study. Int J Clin Health Psychol2023;23(2):100351; doi: 10.1016/j.ijchp.2022.100351
39.
NahviS, AdamsTR, NingY, et al.Effect of varenicline directly observed therapy versus varenicline self-administered therapy on varenicline adherence and smoking cessation in methadone-maintained smokers: A randomized controlled trial. Addiction2021;116(4):902–913; doi: 10.1111/add.15240
40.
NahviS, NingY, SegalKS, et al.Varenicline efficacy and safety among methadone maintained smokers: A randomized placebo-controlled trial. Addiction2014;109(9):1554–1563; doi: 10.1111/add.12631
41.
NaqviNH, RudraufD, DamasioH, et al.Damage to the insula disrupts addiction to cigarette smoking. Science2007;315(5811):531–534; doi: 10.1126/science.1135926
42.
Nieto-CastanonA. General Linear Model. In: Handbook of functional connectivity Magnetic Resonance Imaging methods in CONN. Hilbert Press: 2020; pp. 63–82.
43.
PanY, BiC, YeZ, et al.Tobacco smoking functional networks: A whole-brain connectome analysis in 24 539 individuals. Nicotine Tob Res2025;27(5):917–925; doi: 10.1093/ntr/ntae256
44.
PetersenN, ApostolMR, JordanT, et al.Comparing neuromodulation targets to reduce cigarette craving and withdrawal: A randomized clinical trial. Neuropsychopharmacology2025;50(9):1319–1326; doi: 10.1038/s41386-025-02106-2
45.
RahmaniN, RahimiA, IturraldeK, et al.Attentional bias in tobacco use disorder using eye tracking: A systematic review. Drug Alcohol Depend Rep2024;13:100294; doi: 10.1016/j.dadr.2024.100294
46.
RajabiA, DehghaniM, ShojaeiA, et al.Association between tobacco smoking and opioid use: A meta-analysis. Addict Behav2019;92:225–235; doi: 10.1016/j.addbeh.2018.11.043
47.
RajkowskaG, Goldman-RakicPS. Cytoarchitectonic definition of prefrontal areas in the normal human cortex: II. Variability in locations of areas 9 and 46 and relationship to the Talairach Coordinate System. Cereb Cortex1995;5(4):323–337; doi: 10.1093/cercor/5.4.323
48.
RakeshG, AdamsTG, MoreyRA, et al.Intermittent theta burst stimulation and functional connectivity in people living with HIV/AIDS who smoke tobacco cigarettes: A preliminary pilot study. Front Psychiatry2024;15:1315854; doi: 10.3389/fpsyt.2024.1315854
49.
RakeshG, AlcornJL3rd, KhanalR, et al.Comparing cigarette-cue attentional bias between people with HIV/AIDS and people with opioid use disorder who smoke. Health Psychol Behav Med2023;11(1):2255028; doi: 10.1080/21642850.2023.2255028
50.
RayLA, RocheDJO. Neurobiology of craving: Current findings and new directions. Curr Addict Rep2018;5(2):102–109; doi: 10.1007/s40429-018-0202-2
51.
SchmidtA, DenierN, MagonS, et al.Increased functional connectivity in the resting-state basal ganglia network after acute heroin substitution. Transl Psychiatry2015;5(3):e533; doi: 10.1038/tp.2015.28
52.
ScolariM, Seidl-RathkopfKN, KastnerS. Functions of the human frontoparietal attention network: Evidence from neuroimaging. Curr Opin Behav Sci2015;1:32–39; doi: 10.1016/j.cobeha.2014.08.003
53.
SinghA, Erwin-GrabnerT, SutcliffeG, et al.Default mode network alterations after intermittent theta burst stimulation in healthy subjects. Transl Psychiatry2020;10(1):75; doi: 10.1038/s41398-020-0754-5
54.
SmithPH, WeinbergerAH, ZhangJ, et al.Sex differences in smoking cessation pharmacotherapy comparative efficacy: A network meta-analysis. Nicotine Tob Res2017;19(3):273–281; doi: 10.1093/ntr/ntw144
55.
SuppaA, HuangYZ, FunkeK, et al.Ten years of theta burst stimulation in humans: Established knowledge, unknowns and prospects. Brain Stimul2016;9(3):323–335; doi: 10.1016/j.brs.2016.01.006
56.
SwainJE, HoSS. Early postpartum resting-state functional connectivity for mothers receiving buprenorphine treatment for opioid use disorder: A pilot study. J Neuroendocrinol2019;31(9):e12770; doi: 10.1111/jne.12770
57.
TangY, JiaoX, WangJ, et al.Dynamic functional connectivity within the Fronto-Limbic network induced by intermittent theta-burst stimulation: A pilot study. Front Neurosci2019;13:944; doi: 10.3389/fnins.2019.00944
58.
UptonS, BrownAA, GolzyM, et al.Right inferior frontal gyrus theta-burst stimulation reduces smoking behaviors and strengthens fronto-striatal-limbic resting-state functional connectivity: A randomized crossover trial. Front Psychiatry2023;14:1166912; doi: 10.3389/fpsyt.2023.1166912
59.
VladC, ArnstenJH, NahviS. Achieving smoking cessation among persons with opioid use disorder. CNS Drugs2020;34(4):367–387; doi: 10.1007/s40263-020-00701-z
60.
WangTW, AsmanK, GentzkeAS, et al.Tobacco product use among adults—United States, 2017. MMWR Morb Mortal Wkly Rep2018;67(44):1225–1232; doi: 10.15585/mmwr.mm6744a2
61.
WeidlerC, GramegnaC, MullerD, et al.Resting-state functional connectivity and structural differences between smokers and healthy non-smokers. Sci Rep2024;14(1):6878; doi: 10.1038/s41598-024-57510-3
62.
WeilandBJ, SabbineniA, CalhounVD, et al.Reduced executive and default network functional connectivity in cigarette smokers. Hum Brain Mapp2015;36(3):872–882; doi: 10.1002/hbm.22672
63.
WilliamsNR, SudheimerKD, BentzleyBS, et al.High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain2018;141(3):e18; doi: 10.1093/brain/awx379
64.
WoisardK, SteinbergJL, MaL, et al.Preliminary findings of Weaker Executive Control Network resting state fMRI functional connectivity in opioid use disorder compared to healthy controls. J Addict Res Ther2021;12(10).
65.
WorsleyKJ, MarrettS, NeelinP, et al.A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp1996;4(1):58–73; doi: 10.1002/(SICI)1097-0193(1996)4:1<58::AID-HBM4>3.0.CO;2-O
66.
XuY, WangS, ChenL, et al.Reduced midbrain functional connectivity and recovery in abstinent heroin users. J Psychiatr Res2021;144:168–176; doi: 10.1016/j.jpsychires.2021.10.011
67.
YangW, WangS, LuoJ, et al.Longitudinal resting-state functional connectivity changes in the insular subdivisions of abstinent individuals with opioid use disorder. Psychiatry Res2022a;317:114808; doi: 10.1016/j.psychres.2022.114808
68.
YangW, ZhangM, TangF, et al.Recovery of superior frontal gyrus cortical thickness and resting-state functional connectivity in abstinent heroin users after 8 months of follow-up. Hum Brain Mapp2022b;43(10):3164–3175; doi: 10.1002/hbm.25841
69.
YipSW, LichensteinSD, GarrisonK, et al.Effects of smoking status and state on intrinsic connectivity. Biol Psychiatry Cogn Neurosci Neuroimaging2022;7(9):895–904; doi: 10.1016/j.bpsc.2021.02.004
70.
ZangenA, MosheH, MartinezD, et al.Repetitive transcranial magnetic stimulation for smoking cessation: A pivotal multicenter double-blind randomized controlled trial. World Psychiatry2021;20(3):397–404; doi: 10.1002/wps.20905
ZhangY, ZhongX, ShaoY, et al.Insula connectivity abnormalities predict impulsivity in chronic heroin use disorder: A cross-sectional resting-state fMRI study. Brain Sci2023;13(11):1508; doi: 10.3390/brainsci13111508
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