Neuroimaging studies of cannabidiol and potential neurobiological mechanisms relevant for alcohol use disorders: a systematic review | Journal of Cannabis Research
Arout CA, Haney M, Herrmann ES, Bedi G, Cooper ZDJBJ. A placebo-controlled investigation of the analgesic effects, abuse liability, safety and tolerability of a range of oral cannabidiol doses in healthy humans. Br J Clin Pharmacol. 2022;88(1):347–55.
Bach DR, Friston KJ, Dolan RJJI. Analytic measures for quantification of arousal from spontaneous skin conductance fluctuations. Int J Psychophysiol. 2010;76(1):52–5.
Barbier EL, Lamalle L, Décorps M. Methodology of brain perfusion imaging. J Magn Reson Imaging. 2001;13(4):496–520.
Bergamaschi MM, Queiroz RHC, Chagas MHN, De Oliveira DCG, De Martinis BS, Kapczinski F, Nardi AE. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacol. 2011;36(6):1219–26.
Berger M, Li E, Rice S, Davey CG, Ratheesh A, Adams S, Spelman T, Kevin R. Cannabidiol for treatment-resistant anxiety disorders in young people an open-label trial. J Clin Psychiatry. 2022;83(5):42111.
Bhattacharyya S, Crippa JA, Allen P, Martin-Santos R, Borgwardt S, Fusar-Poli P, McGuire PK. Induction of psychosis by Δ9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Arch Gen Psychiatry. 2012;69(1):27–36. https://doi.org/10.1001/archgenpsychiatry.2011.161.
Bhattacharyya S, Falkenberg I, Martin-Santos R, Atakan Z, Crippa JA, Giampietro V, McGuire P 2014. Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience. Neuropsychopharmacology. 23. https://doi.org/10.1038/npp.2014.258
Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martin-Santos R, Nosarti C, O’Carroll C, McGuire P. Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol a neural basis for the effects of Cannabis sativa on learning and psychosis. Arch Gen Psychiatry. 2009;66(4):442–51. https://doi.org/10.1001/archgenpsychiatry.2009.17.
Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, McGuire PK. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacol. 2010;35(3):764–74. https://doi.org/10.1038/npp.2009.184.
Bhattacharyya S, Wilson R, Appiah-Kusi E, et al. Effect of cannabidiol on medial temporal, midbrain, and striatal dysfunction in people at clinical high risk of psychosis: A randomized clinical trial. JAMA Psychiat. 2018a;75(11):1107–17. https://doi.org/10.1001/jamapsychiatry.2018.2309.
Bloomfield MAP, Green SF, Hindocha C, Yamamori Y, Yim JLL, Jones APM, Freeman TP. The effects of acute cannabidiol on cerebral blood flow and its relationship to memory: An arterial spin labelling magnetic resonance imaging study. J Psychopharmacol. 2020;34(9):981–9. https://doi.org/10.1177/0269881120936419.
Bloomfield MAP, Yamamori Y, Hindocha C, Jones APM, Yim JLL, Walker HR, Freeman TP. The acute effects of cannabidiol on emotional processing and anxiety: a neurocognitive imaging study. Psychopharmacol. 2022;239(5):1539–49. https://doi.org/10.1007/s00213-022-06070-3.
Borgwardt SJ, Allen P, Bhattacharyya S, Fusar-Poli P, Crippa JA, Seal ML, McGuire PK. Neural Basis of DELTA-9-Tetrahydrocannabinol and Cannabidiol: Effects During Response Inhibition. Biological Psychiatry. 2008;64(11):966–73. https://doi.org/10.1016/j.biopsych.2008.05.011.
Brown S, Martinez MJ, Parsons LMJN. Passive music listening spontaneously engages limbic and paralimbic systems. Neuroreport. 2004;15(13):2033–7.
Campos AC, Guimarães FSJP. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacol (Berl). 2008;199(2):223–30.
Chastain G. Alcohol, Neurotransmitter Systems, and Behavior. J Gen Psychol. 2006;133(4):329–35. https://doi.org/10.3200/GENP.133.4.329-335.
Corroon J, Felice. The Endocannabinoid System and its Modulation by Cannabidiol (CBD). Altern Ther Health Med. 2019;25:6–14.
Crippa JA, Guimarães FS, Campos AC, Zuardi AW. Translational investigation of the therapeutic potential of cannabidiol (CBD): toward a new age. Front Immunol. 2018;9:2009.
Crippa JA, Zuardi AW, Garrido GE, Wichert-Ana L, Guarnieri R, Ferrari L, Filho Busatto G. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology. 2004;29(2):417–26. https://doi.org/10.1038/sj.npp.1300340.
Critchley HD. The human cortex responds to an interoceptive challenge. Proc Natl Acad Sci U S A. 2004;101(17):6333–4.
Davies C, Appiah-Kusi E, Wilson R, Blest-Hopley G, Bossong MG, Valmaggia L, Bhattacharyya S. Altered relationship between cortisol response to social stress and mediotemporal function during fear processing in people at clinical high risk for psychosis: a preliminary report. Eur Arch Psychiatry Clin Neurosci. 2022;272(3):461–75. https://doi.org/10.1007/s00406-021-01318-z.
Davies C, Wilson R, Appiah-Kusi E, Blest-Hopley G, Brammer M, Perez J, Bhattacharyya S. A single dose of cannabidiol modulates medial temporal and striatal function during fear processing in people at clinical high risk for psychosis. Transl Psychiatry. 2020;10(1):311. https://doi.org/10.1038/s41398-020-0862-2.
Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurology. 2016;15(3):270–8. https://doi.org/10.1016/S1474-4422(15)00379-8.
Fagundo AB, De la Torre R, Jiménez-Murcia S, Agüera Z, Pastor A, Casanueva FF, Pino-Gutiérrez A. Modulation of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) on executive functions in humans. PLoS One. 2013;8(6):e66387.
Fitzgerald ML, Shobin E, Pickel VMJP. Cannabinoid modulation of the dopaminergic circuitry: implications for limbic and striatal output. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38(1):21–9.
Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci. 2007;8(9):700–11.
Fusar-Poli P, Allen P, Bhattacharyya S, Crippa JA, Mechelli A, Borgwardt S, McGuire P. Modulation of effective connectivity during emotional processing by Delta 9-tetrahydrocannabinol and cannabidiol. Int J Neuropsychopharmacol. 2010;13(4):421–32. https://doi.org/10.1017/s1461145709990617.
Fusar-Poli P, Crippa J, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, McGuire PK. Distinct effects of A9-Tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch General Psychiatry. 2009;66(1):95–105. https://doi.org/10.1001/archgenpsychiatry.2008.519.
Geisler S, Wise RA. Functional implications of glutamatergic projections to the ventral tegmental area. Rev Neurosci. 2008;19(4–5):227–44.
George O, Sanders C, Freiling J, Grigoryan E, Vu S, Allen CD, Koob GFJP. Recruitment of medial prefrontal cortex neurons during alcohol withdrawal predicts cognitive impairment and excessive alcohol drinking. Proc Natl Acad Sci U S A. 2012;109(44):18156–61.
Gilman JM, Ramchandani VA, Davis MB, Bjork JM, Hommer DW. Why we like to drink: a functional magnetic resonance imaging study of the rewarding and anxiolytic effects of alcohol. J Neurosci. 2008;28(18):4583–91. https://doi.org/10.1523/JNEUROSCI.0086-08.2008.
Goulden N, Khusnulina A, Davis NJ, Bracewell RM, Bokde AL, McNulty JP, Mullins PGJN. The salience network is responsible for switching between the default mode network and the central executive network: replication from DCM. Neuroimage. 2014;99:180–90.
Grimm O, Loffler M, Kamping S, Hartmann A, Rohleder C, Leweke M, Flor H. Probing the endocannabinoid system in healthy volunteers: Cannabidiol alters fronto-striatal resting-state connectivity. Eur Neuropsychopharmacol. 2018;28(7):841–9. https://doi.org/10.1016/j.euroneuro.2018.04.004.
Griswold MG, Fullman N, Hawley C, Arian N, Zimsen SRM, Tymeson HD, Gakidou E. Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. 2018;392(10152):1015–35. https://doi.org/10.1016/s0140-6736(18)31310-2.
Haber P, Riordan B, Morley KC. Providing care and management for patients with alcohol problems: treatments, interventions, relapse prevention, aftercare, and long-term follow-up. Med J Aust. 2021;215(Suppl 7):S3–32.
Haney M, Malcolm RJ, Babalonis S, Nuzzo PA, Cooper ZD, Bedi G, Sparenborg S. Oral cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of smoked cannabis. Neuropsychopharmacol. 2016;41(8):1974–82.
Hargreaves R, Hoppin J, Sevigny J, Patel S, Chiao P, Klimas M, Verma A. Optimizing central nervous system drug development using molecular imaging. Clin Pharmacol Ther. 2015;98(1):47–60.
Heeger DJ, Ress D. What does fMRI tell us about neuronal activity? Nat Rev Neurosci. 2002;3(2):142–51.
Hurd YL, Spriggs S, Alishayev J, Winkel G, Gurgov K, Kudrich C, Salsitz EJ. Cannabidiol for the reduction of cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder: a double-blind randomized placebo-controlled trial. Am J Psychiatry. 2019;176(11):911–22.
Jadoon KA, Tan GD, O’Sullivan SE. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight. 2017;2(12):e93760. https://doi.org/10.1172/jci.insight.93760.
Jansen JM, van den Heuvel OA, van der Werf YD, De Wit SJ, Veltman DJ, Van Den Brink W, Goudriaan AE. Emotion processing, reappraisal, and craving in alcohol dependence: a functional magnetic resonance imaging study. Front Psychiatry. 2019;10:227.
Jentsch JD, Taylor JR. Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacol. 1999;146(4):373–90.
Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML. A double dissociation of ventromedial prefrontal cortical responses to sad and happy stimuli in depressed and healthy individuals. Biol Psychiatry. 2005;58(6):495–503.
Knutson B, Greer SM. Anticipatory affect: neural correlates and consequences for choice. Philos Trans R Soc Lond B Biol Sci. 2008;363(1511):3771–86.
Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760–73. https://doi.org/10.1016/s2215-0366(16)00104-8.
Kopel R, Sladky R, Laub P, Koush Y, Robineau F, Hutton C, Scharnowski FJN. No time for drifting: Comparing performance and applicability of signal detrending algorithms for real-time fMRI. Neuroimage. 2019;191:421–9.
Lapish CC, Seamans JK, Judson Chandler L. Glutamate-dopamine cotransmission and reward processing in addiction. Alcohol Clin Exp Res. 2006;30(9):1451–65.
Laprairie R, Bagher A, Kelly M, Denovan-Wright E. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172(20):4790–805.
Lawn W, Hill J, Hindocha C, Yim J, Yamamori Y, Jones G, Bloomfield MA. The acute effects of cannabidiol on the neural correlates of reward anticipation and feedback in healthy volunteers. J Psychopharmacol. 2020;34(9):969–80. https://doi.org/10.1177/0269881120944148.
Leweke F, Piomelli D, Pahlisch F, Muhl D, Gerth C, Hoyer C, Koethe D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translational Psychiatry. 2012;2(3):e94–e94.
Linden DE, Prvulovic D, Formisano E, Völlinger M, Zanella FE, Goebel R, Dierks T. The functional neuroanatomy of target detection: an fMRI study of visual and auditory oddball tasks. Cereb Cortex. 1999;9(8):815–23.
Mandolini GM, Lazzaretti M, Pigoni A, Oldani L, Delvecchio G, Brambilla P. Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview. Epidemiol Psychiatric Sci. 2018;27(4):327–35. https://doi.org/10.1017/S2045796018000239.
McCartney D, Suraev AS, Doohan PT, Irwin C, Kevin RC, Grunstein RR, Kevin RC, McGregor IS. Effects of cannabidiol on simulated driving and cognitive performance: a dose-ranging randomised controlled trial. J Psychopharmacol. 2022;36(12):1338–49.
McCutcheon RA, Nour MM, Dahoun T, Jauhar S, Pepper F, Expert P, Mehta MA. Mesolimbic dopamine function is related to salience network connectivity: an integrative positron emission tomography and magnetic resonance study. Biol Psychiatry. 2019;85(5):368–78.
Mechoulam R, Peters M, Murillo-Rodriguez E, Hanuš LO. Cannabidiol – Recent Advances. Chem Biodivers. 2007;4(8):1678–92. https://doi.org/10.1002/cbdv.200790147.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med. 2009;3(3):e123-130.
Morley KC. Commentary on Donoghue: Low prescribing rates of pharmacotherapy for alcohol use disorder limit potential public health impact. Addiction. 2021. https://doi.org/10.1111/add.15532.
Morley KC, Perry CJ, Watt J, Hurzeler T, Leggio L, Lawrence AJ, Haber P. New approved and emerging pharmacological approaches to alcohol use disorder: a review of clinical studies. Expert Opin Pharmacother. 2021;22:1–13. https://doi.org/10.1080/14656566.2021.1892641.
Morris JS, Frith CD, Perrett DI, Rowland D, Young AW, Calder AJ, Dolan RJJN. a differential neural response in the human amygdala to fearful and happy facial expressions. Nature. 1996;383(6603):812–5.
Naqvi NH, Rudrauf D, Damasio H, Bechara AJS. Damage to the Insula Disrupts Addiction to Cigarette Smoking. Science. 2007;315(5811):531–4.
Nathan PJ, Phan KL, Harmer CJ, Mehta MA, Bullmore ET. Increasing pharmacological knowledge about human neurological and psychiatric disorders through functional neuroimaging and its application in drug discovery. Curr Opin Pharmacol. 2014;14:54–61.
O’Daly OG, Trick L, Scaife J, Marshall J, Ball D, Phillips ML, Duka T. Withdrawal-associated increases and decreases in functional neural connectivity associated with altered emotional regulation in alcoholism. Neuropsychopharmacol. 2012;37(10):2267–76. https://doi.org/10.1038/npp.2012.77.
Oscar-Berman M, Marinković K. Alcohol: effects on neurobehavioral functions and the brain. Neuropsychol Rev. 2007;17(3):239–57.
Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain A review and meta-analysis (2000). Neurophysiol Clin. 2000;30(5):263–88.
Pretzsch CM, Freyberg J, Voinescu B, Lythgoe D, Horder J, Mendez MA, Heasman M. Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder. Neuropsychopharmacology. 2019;44(8):1398–405.
Pretzsch CM, Voinescu B, Mendez MA, Wichers R, Ajram L, Ivin G, McAlonan GM. The effect of cannabidiol (CBD) on low-frequency activity and functional connectivity in the brain of adults with and without autism spectrum disorder (ASD). J Psychopharmacol. 2019;33(9):1141–8. https://doi.org/10.1177/0269881119858306.
Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci. 2001;98(2):676–82.
Ren Y, Whittard J, Higuera-Matas A, Morris CV, Hurd YL. Cannabidiol, a Nonpsychotropic Component of Cannabis, Inhibits Cue-Induced Heroin Seeking and Normalizes Discrete Mesolimbic Neuronal Disturbances. J Neurosci. 2009;29(47):14764–9. https://doi.org/10.1523/JNEUROSCI.4291-09.2009.
Rubia K, Smith AB, Brammer MJ, Taylor E. Temporal lobe dysfunction in medication-naive boys with attention-deficit/hyperactivity disorder during attention allocation and its relation to response variability. Biol Psychiatry. 2007;62(9):999–1006.
Rubia K, Smith AB, Woolley J, Nosarti C, Heyman I, Taylor E, Brammer M. Progressive increase of frontostriatal brain activation from childhood to adulthood during event-related tasks of cognitive control. Hum Brain Mapp. 2006;27(12):973–93.
Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037–43.
Schoedel KA, Szeto I, Setnik B, Sellers EM, Levy-Cooperman N, Mills C. Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: a randomized, double-blind, controlled trial. Epilepsy Behav. 2018;88:162–71.
Scopinho AA, Guimarães FS, Corrêa FM, Resstel LB. Cannabidiol inhibits the hyperphagia induced by cannabinoid-1 or serotonin-1A receptor agonists. Pharmacol Biochem Behav. 2011;98(2):268–72.
Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, Greicius MD. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci. 2007;27(9):2349–56.
Skelley JW, Deas CM, Curren Z, Ennis J. Use of cannabidiol in anxiety and anxiety-related disorders. J Am Pharm Assoc. 2020;60(1):253–61. https://doi.org/10.1016/j.japh.2019.11.008.
Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM. RoB 2: a revised tool for assessing risk of bias in randomised trials. bmj. 2019:366.
Talwar A, Estes E, Aparasu R, Reddy DS. Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: A systematic review and meta-analysis. Exp Neurol. 2022;359:114238.
Tottenham N, Tanaka JW, Leon AC, McCarry T, Nurse M, Hare TA, Nelson C. The NimStim set of facial expressions: Judgments from untrained research participants. Psychiatry Res. 2009;168(3):242–9. https://doi.org/10.1016/j.psychres.2008.05.006.
Ujváry I, Hanuš L. Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res. 2016;1(1):90–101.
Vitale RM, Iannotti FA, Amodeo P. The (poly) pharmacology of cannabidiol in neurological and neuropsychiatric disorders: Molecular mechanisms and targets. Int J Mol Sci. 2021;22(9):4876.
Viudez-Martínez A, García-Gutiérrez MS, Fraguas-Sánchez AI, Torres-Suárez AI, Manzanares J. Effects of cannabidiol plus naltrexone on motivation and ethanol consumption. Br J Pharmacol. 2018a;175(16):3369–78. https://doi.org/10.1111/bph.14380.
Viudez-Martínez A, García-Gutiérrez MS, Manzanares J. Cannabidiol regulates the expression of hypothalamus-pituitary-adrenal axis-related genes in response to acute restraint stress. J Psychopharmacol. 2018;32(12):1379–84.
Viudez-Martínez A, García-Gutiérrez MS, Navarrón CM, Morales-Calero MI, Navarrete F, Torres-Suárez AI, Manzanares J. Cannabidiol reduces ethanol consumption, motivation and relapse in mice. Addict Biol. 2018c;23(1):154–64. https://doi.org/10.1111/adb.12495.
Wall MB, Freeman TP, Hindocha C, Demetriou L, Ertl N, Freeman AM, Bloomfield MA. Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain. J Psychopharmacol. 2022;36(6):732–44.
Wechsler D. Wechsler memory scale-revised. New York: The psychological corporation; 1987.
WHO. Global status report on alcohol and health. Geneva: World Health Organisation; 2018.
WHO. Global alcohol action plan 2022–2030 to strengthen implementation of the Global Strategy to Reduce the Harmful Use of Alcohol. Geneva: World Health Organisation; 2021.
Wilson R, Bossong MG, Appiah-Kusi E, Petros N, Brammer M, Perez J, Bhattacharyya S. Cannabidiol attenuates insular dysfunction during motivational salience processing in subjects at clinical high risk for psychosis. Transl Psychiatry. 2019;9(1):1–10.
Wilson R, Bossong MG, Appiah-Kusi E, Petros N, Brammer M, Perez J, Bhattacharyya S. Cannabidiol attenuates insular dysfunction during motivational salience processing in subjects at clinical high risk for psychosis. Transl Psychiatry. 2019;9(1):203. https://doi.org/10.1038/s41398-019-0534-2.
Winton-Brown T, Allen P, Bhattacharrya S, Borgwardt SJ, Fusar-Poli P, Crippa JA, McGuire PK. Modulation of Auditory and Visual Processing by Delta-9-Tetrahydrocannabinol and Cannabidiol: an fMRI Study. Neuropsychopharmacol. 2011;36(7):1340–8. https://doi.org/10.1038/npp.2011.17.
Wong DF, Tauscher J, Gründer G. The role of imaging in proof of concept for CNS drug discovery and development. Neuropsychopharmacol. 2009;34(1):187–203.
Worsley KJ, Friston KJ. Analysis of fMRI time-series revisited—again. Neuroimage. 1995;2(3):173–81.
Wylie GR, Yao B, Genova HM, Chen MH, DeLuca J. Using functional connectivity changes associated with cognitive fatigue to delineate a fatigue network. Sci Rep. 2020;10(1):1–12.