THC disrupts the DMN, and the PCC is a key brain region involved in the subjective experience of THC intoxication. CBD restores disruption of the salience network by THC, which may explain its potential to treat disorders of salience such as psychosis and addiction.

Reductions in functional connectivity (relative to placebo) were seen in the DMN (PCC+) and SAL (AI+) networks for both strains of cannabis, with spatially dissociable effects. Across the entire salience network (AI+), Cann−CBD reduced connectivity relative to Cann+CBD. The PCC in the DMN was specifically disrupted by Cann−CBD, and this effect correlated with subjective drug effects, including feeling ‘stoned’ and ‘high’.

Seventeen healthy volunteers (experienced with cannabis, but not regular users) underwent three drug treatments and scanning sessions. Treatments were cannabis containing THC (Cann−CBD; 8 mg THC), cannabis containing THC with CBD (Cann+CBD; 8 mg THC + 10 mg CBD), and matched placebo cannabis. Seed-based resting-state functional connectivity analyses were performed on three brain networks: the default mode (DMN; defined by positive connectivity with the posterior cingulate cortex: PCC+), executive control (ECN; defined by negative connectivity with the posterior cingulate cortex: PCC−) and salience (SAL; defined by positive connectivity with the anterior insula: AI+) network.

We examined the effects of two strains of cannabis and placebo on the human brain’s resting-state networks using fMRI.

Two major constituents of cannabis are Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the main psychoactive component; CBD may buffer the user against the harmful effects of THC.

References

Benjamini, Y, Hochberg, Y ( 1995 ) Controlling the false discovery rate: A practical and powerful approach to multiple testing . J R Stat Soc 57: 289 – 300 .

Google Scholar

Bergamaschi, MM, Queiroz, RHC, Chagas, MHN. ( 2011 ) Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients . Neuropsychopharmacology 36: 1219 – 1226 .

Google Scholar Crossref | Medline | ISI

Bhattacharyya, S, Crippa, JA, Allen, P. ( 2012 ) Induction of psychosis by Δ9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing . Arch Gen Psychiatry 69: 27 – 36 .

Google Scholar Crossref | Medline

Bhattacharyya, S, Falkenberg, I, Martin-Santos, R. ( 2014 ) Cannabinoid modulation of functional connectivity within regions processing attentional salience . Neuropsychopharmacology 40: 1343 – 1352 .

Google Scholar Crossref | Medline

Bhattacharyya, S, Morrison, PD, Fusar-Poli, P. ( 2010 ) Opposite effects of Δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology . Neuropsychopharmacology 35: 764 – 774 .

Google Scholar Crossref | Medline | ISI

Biswal, BB, Mennes, M, Zuo, X-N. ( 2010 ) Toward discovery science of human brain function . Proc Natl Acad Sci U S A 107: 4734 – 4739 .

Google Scholar Crossref | Medline | ISI

Bossong, MG, Jansma, JM, van Hell, HH. ( 2013 ) Default mode network in the effects of Δ9-Tetrahydrocannabinol (THC) on human executive function . PLoS One 8: 1 – 10 .

Google Scholar Crossref

Bossong, MG, Van Berckel, BNM, Boellaard, R. ( 2009 ) Δ9-tetrahydrocannabinol induces dopamine release in the human striatum . Neuropsychopharmacology 34: 759 – 766 .

Google Scholar Crossref | Medline | ISI

Bourke, JH, Wall, MB ( 2015 ) phMRI: Methodological considerations for mitigating potential confounding factors . Front Neurosci 9: 1 – 7 .

Google Scholar Crossref | Medline

Buckner, RL, Andrews-Hanna, JR, Schacter, DL ( 2008 ) The brain’s default network: Anatomy, function, and relevance to disease . Ann N Y Acad Sci 1124: 1 – 38 .

Google Scholar Crossref | Medline | ISI

Burns, HD, Van Laere, K, Sanabria-Bohórquez, S. ( 2007 ) [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor . Proc Natl Acad Sci U S A 104: 9800 – 9805 .

Google Scholar Crossref | Medline | ISI

Carhart-Harris, RL, Kevin, M, Robert, L. ( 2015 ) The effects of acute administered 3,4-methylenedioxymethamphetamine on spontaneous brain function in healthy volunteers measured with arterial spin labelling and blood oxygen level-dependent resting-state functional connectivity . Biol Psychiatry 78: 554 – 562 .

Google Scholar Crossref | Medline

Cole, DM, Smith, SM, Beckmann, CF ( 2010 ) Advances and pitfalls in the analysis and interpretation of resting-state FMRI data . Front Syst Neurosci 4: 8 .

Google Scholar Medline

Comninos, AN, Demetriou, L, Wall, MB. ( 2018 ) Modulations of human resting brain connectivity by kisspeptin enhance sexual and emotional functions . JCI Insight 3. pii: 121958 .

Google Scholar Crossref | Medline

Curran, HV, Brignell, C, Fletcher, S. ( 2002 ) Cognitive and subjective dose-response effects of acute oral Δ9-tetrahydrocannabinol (THC) in infrequent cannabis users . Psychopharmacology 164: 61 – 70 .

Google Scholar Crossref | Medline | ISI

Curran, HV, Freeman, TP, Mokrysz, C. ( 2016 ) Keep off the grass? Cannabis, cognition and addiction . Nat Rev Neurosci 17: 293 – 306 .

Google Scholar Crossref | Medline

De Luca, M, Beckmann, CF, De Stefano, N. ( 2006 ) fMRI resting state networks define distinct modes of long-distance interactions in the human brain . Neuroimage 29: 1359 – 1367 .

Google Scholar Crossref | Medline | ISI

Demetriou, L, Kowalczyk, OS, Tyson, G. ( 2018 ) A comprehensive evaluation of increasing temporal resolution with multiband-accelerated sequences and their effects on statistical outcome measures in fMRI . Neuroimage 176: 404 – 416 .

Google Scholar Crossref | Medline

Demirakca, T, Sartorius, A, Ende, G. ( 2011 ) Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol . Drug Alcohol Depend 114: 242 – 245 .

Google Scholar Medline

Di Forti, M, Morgan, C, Dazzan, P. ( 2009 ) High potency cannabis and the risk of psychosis . Br J Psychiatry 195: 488 – 491 .

Google Scholar Crossref | Medline | ISI

D’Souza, DC, Perry, E, MacDougall, L. ( 2004 ) The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: Implications for psychosis . Neuropsychopharmacology 29: 1558 – 1572 .

Google Scholar Crossref | Medline | ISI

ElSohly, MA, Mehmedic, Z, Foster, S. ( 2016 ) Changes in cannabis potency over the last 2 decades (1995–2014): Analysis of current data in the United States . Biol Psychiatry 79: 613 – 619 .

Google Scholar Crossref | Medline

Englund, A, Morrison, PD, Nottage, J. ( 2013 ) Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment . J Psychopharmacol 27: 19 – 27 .

Google Scholar SAGE Journals | ISI

Fox, MD, Raichle, ME ( 2007 ) Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging . Nat Rev Neurosci 8: 700 – 711 .

Google Scholar Crossref | Medline | ISI

Fox, MD, Snyder, AZ, Vincent, JL. ( 2005 ) The human brain is intrinsically organized into dynamic, anticorrelated functional networks . Proc Natl Acad Sci U S A 102: 9673 – 9678 .

Google Scholar Crossref | Medline | ISI

Freeman, TP, Winstock, AR ( 2015 ) Examining the profile of high-potency cannabis and its association with severity of cannabis dependence . Psychol Med 45: 3181 – 3189 .

Google Scholar Crossref | Medline

Freeman, TP, Morgan, CJA, Hindocha, C. ( 2014 ) Just say ‘know’: How do cannabinoid concentrations influence users’ estimates of cannabis potency and the amount they roll in joints? Addiction 109: 1686 – 1694 .

Google Scholar Crossref | Medline | ISI

Freeman, TP, Pope, RA, Wall, MB. ( 2017 ) Cannabis dampens the effects of music in brain regions sensitive to reward and emotion . Int J Neuropsychopharmacol 21: 21 – 32 .

Google Scholar Crossref

Freeman, TP, van der Pol, P, Kuijpers, W. ( 2018 ) Changes in cannabis potency and first-time admissions to drug treatment: A 16-year study in the Netherlands . Psychol Med 48: 2346 – 2352 .

Google Scholar Crossref | Medline

Goulden, N, Khusnulina, A, Davis, NJ. ( 2014 ) The salience network is responsible for switching between the default mode network and the central executive network: Replication from DCM . Neuroimage 99: 180 – 190 .

Google Scholar Crossref | Medline | ISI

Grimm, O, Löffler, M, Kamping, S. ( 2018 ) Probing the endocannabinoid system in healthy volunteers: Cannabidiol alters fronto-striatal resting-state connectivity . Euro Neuropsychopharmacol 28: 841 – 849 .

Google Scholar Crossref | Medline

Hindocha, C, Freeman, TP, Schafer, G. ( 2015 ) Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: A randomised, double-blind, placebo-controlled study in cannabis users . Euro Neuropsychopharmacol 25: 325 – 334 .

Google Scholar Crossref | Medline

Hindocha, C, Wollenberg, O, Carter Leno, V. ( 2014 ) Emotional processing deficits in chronic cannabis use: A replication and extension . J Psychopharmacol 28: 466 – 471 .

Google Scholar SAGE Journals | ISI

Hirvonen, J, Goodwin, RS, Li, C-T. ( 2012 ) Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers . Mol Psychiatry 17: 642 – 649 .

Google Scholar Crossref | Medline | ISI

Iannetti, GD, Wise, RG ( 2007 ) BOLD functional MRI in disease and pharmacological studies: Room for improvement? Magn Reson Imaging 25: 978 – 988 .

Google Scholar Crossref | Medline | ISI

Kaelen, M, Roseman, L, Kahan, J. ( 2016 ) LSD modulates music-induced imagery via changes in parahippocampal connectivity . Euro Neuropsychopharmacol 26: 1099 – 1109 .

Google Scholar Crossref | Medline | ISI

Kapur, S ( 2003 ) Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia . Am J Psychiatry 160: 13 – 23 .

Google Scholar Crossref | Medline | ISI

Klumpers, LE, Cole, DM, Khalili-Mahani, N. ( 2012 ) Manipulating brain connectivity with δ9-tetrahydrocannabinol: A pharmacological resting state FMRI study . Neuroimage 63: 1701 – 1711 .

Google Scholar Crossref | Medline

Lawn, W, Freeman, TP, Pope, RA. ( 2016 ) Acute and chronic effects of cannabinoids on effort-related decision-making and reward learning: An evaluation of the cannabis ‘amotivational’ hypotheses . Psychopharmacology 233: 3537 – 3552 .

Google Scholar Crossref | Medline

Leweke, FM, Piomelli, D, Pahlisch, F. ( 2012 ) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia . Transl Psychiatry 2: e94 .

Google Scholar Crossref | Medline | ISI

Mokrysz, C, Freeman, TP, Korkki, S. ( 2016 ) Are adolescents more vulnerable to the harmful effects of cannabis than adults? A placebo-controlled study in human males . Transl Psychiatry 6: e961 .

Google Scholar Crossref | Medline

Morgan, CJA, Curran, HV ( 2008 ) Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis . Br J Psychiatry 192: 306 – 307 .

Google Scholar Crossref | Medline | ISI

Morgan, CJA, Freeman, TP, Schafer, GL. ( 2010 ) Cannabidiol attenuates the appetitive effects of Δ9-tetrahydrocannabinol in humans smoking their chosen cannabis . Neuropsychopharmacology 35: 1879 – 1885 .

Google Scholar Crossref | Medline | ISI

Morgan, CJA, Gardener, C, Schafer, G. ( 2012 ) Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being . Psychol Med 42: 391 – 400 .

Google Scholar Crossref | Medline

Morgan, CJA, Page, E, Schaefer, C. ( 2013 ) Cerebrospinal fluid anandamide levels, cannabis use and psychotic-like symptoms . Br J Psychiatry 202: 381 – 382 .

Google Scholar Crossref | Medline

Niesink, RJM, van Laar, MW ( 2013 ) Does cannabidiol protect against adverse psychological effects of THC? Front Psychiatry 4: 130 .

Google Scholar Crossref | Medline

Niesink, RJM, Rigter, S, Koeter, MW. ( 2015 ) Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005–15 . Addiction 110: 1941 – 1950 .

Google Scholar Crossref | Medline

Orr, C, Morioka, R, Behan, B. ( 2013 ) Altered resting-state connectivity in adolescent cannabis users . Am J Drug Alcohol Abuse 39: 372 – 381 .

Google Scholar Crossref | Medline | ISI

Passow, S, Specht, K, Adamsen, TC. ( 2015 ) Default-mode network functional connectivity is closely related to metabolic activity . Hum Brain Mapp 36: 2027 – 2038 .

Google Scholar Crossref | Medline | ISI

Pertwee, RG ( 2008 ) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin . Br J Pharmacol 153: 199 – 215 .

Google Scholar Crossref | Medline | ISI

Ramaekers, JG, Kauert, G, Van Ruitenbeek, P. ( 2006 ) High-potency marijuana impairs executive function and inhibitory motor control . Neuropsychopharmacology 31: 2296 – 2303 .

Google Scholar Crossref | Medline | ISI

Ramaekers, JG, van Wel, JH, Spronk, D. ( 2016 ) Cannabis and cocaine decrease cognitive impulse control and functional corticostriatal connectivity in drug users with low activity DBH genotypes . Brain Imaging Behav 10: 1254 – 1263 .

Google Scholar Crossref | Medline

Robinson, T, Berridge, K ( 1993 ) The neural basis of drug craving: An incentive-sensitization theory of addiction . Brain Res Rev 8: 247 – 291 .

Google Scholar Crossref

Robinson, TE, Berridge, KC ( 2001 ) Incentive-sensitization and addiction . Addiction 96: 103 – 114 .

Google Scholar Crossref | Medline | ISI

Rzepa, E, Tudge, L, McCabe, C ( 2016 ) The CB1 neutral antagonist tetrahydrocannabivarin reduces default mode network and increases executive control network resting state functional connectivity in healthy volunteers . Int J Neuropsychopharmacol 19: pyv092 .

Google Scholar Crossref

Seeley, WW, Menon, V, Schatzberg, AF. ( 2007 ) Dissociable intrinsic connectivity networks for salience processing and executive control . J Neurosci 27: 2349 – 2356 .

Google Scholar Crossref | Medline | ISI

Smith, SM, Fox, PT, Miller, KL. ( 2009 ) Correspondence of the brain’s functional architecture during activation and rest . Proc Natl Acad Sci U S A 106: 13040 – 13045 .

Google Scholar Crossref | Medline | ISI

Sridharan, D, Levitin, DJ, Menon, V ( 2008 ) A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks . Proc Natl Acad Sci U S A 105: 12569 – 12574 .

Google Scholar Crossref | Medline | ISI

van Hell, HH, Bossong, MG, Jager, G. ( 2011 ) Evidence for involvement of the insula in the psychotropic effects of THC in humans: A double-blind, randomized pharmacological MRI study . Int J Neuropsychopharmacol 14: 1377 – 1388 .

Google Scholar Crossref | Medline

Winton-Brown, TT, Allen, P, Bhattacharyya, S. ( 2011 ) Modulation of auditory and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: An fMRI study . Neuropsychopharmacology 36: 1340 – 1348 .

Google Scholar Crossref | Medline | ISI