Abstract
Rationale
Mismatch negativity (MMN) is a candidate endophenotype for schizophrenia subserved by N-methyl-D-aspartate receptor (NMDAR) function and there is increasing evidence that prolonged cannabis use adversely affects MMN generation. Few human studies have investigated the acute effects of cannabinoids on brain-based biomarkers of NMDAR function and synaptic plasticity.
Objectives
The current study investigated the acute effects of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) alone and in combination on the mismatch negativity (MMN).
Methods
In a randomised, double-blind, crossover placebo-controlled study, 18 frequent and 18 less-frequent cannabis users underwent 5 randomised drug sessions administered via vaporiser: (1) placebo; (2) THC 8 mg; (3) CBD 400 mg; (4) THC 8 mg + CBD 4 mg [THC + CBDlow]; (5) THC 12 mg + CBD 400 mg [THC + CBDhigh]. Participants completed a multifeature MMN auditory oddball paradigm with duration, frequency and intensity deviants (6% each).
Results
Relative to placebo, both THC and CBD were observed to increase duration and intensity MMN amplitude in less-frequent users, and THC also increased frequency MMN in this group. The addition of low-dose CBD added to THC attenuated the effect of THC on duration and intensity MMN amplitude in less-frequent users. The same pattern of effects was observed following high-dose CBD added to THC on duration and frequency MMN in frequent users.
Conclusions
The pattern of effects following CBD combined with THC on MMN may be subserved by different underlying neurobiological interactions within the endocannabinoid system that vary as a function of prior cannabis exposure. These results highlight the complex interplay between the acute effects of exogenous cannabinoids and NMDAR function. Further research is needed to determine how this process normalises after the acute effects dissipate and following repeated acute exposure.
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References
Aas IHM (2011) Guidelines for rating Global Assessment of Functioning (GAF). Ann Gen Psychiatry 10 https://doi.org/10.1186/1744-859X-10-2
Araque A, Castillo PE, Manzoni OJ, Tonini R (2017) Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology 124:13–24. https://doi.org/10.1016/j.neuropharm.2017.06.017
Ashton JC (2019) Is Cannabis Harmless? Focus on Brain Function. Curr Drug Res Rev 11:33–39. https://doi.org/10.2174/2589977511666180809165622
Avissar M, Javitt D (2018) Mismatch negativity: A simple and useful biomarker of N-methyl-d-aspartate receptor (NMDAR)-type glutamate dysfunction in schizophrenia. Schizophr Res 191:1–4. https://doi.org/10.1016/j.schres.2017.11.006
Avissar M, Xie S, Vail B, Lopez-Calderon J, Wang Y, Javitt DC (2018) Meta-analysis of mismatch negativity to simple versus complex deviants in schizophrenia. Schizophr Res 191:25–34. https://doi.org/10.1016/j.schres.2017.07.009
Barfi E et al (2021) The role of Tetrahydrocannabinol in inducing disrupted signaling cascades, hippocampal atrophy and memory defects. J Chem Neuroanat 113:101943. https://doi.org/10.1016/j.jchemneu.2021.101943
Barkus EJ, Stirling J, Hopkins RS, Lewis S (2006) Cannabis-induced psychosis-like experiences are associated with high schizotypy. Psychopathology 39:175–178
Batalla A et al (2014) Neuroimaging studies of acute effects of THC and CBD in humans and animals: a systematic review. Curr Pharm Des 20:2168–2185. https://doi.org/10.2174/13816128113199990432
Beale C et al (2018) Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users. Cannabis Cannabinoid Res 3:94–107. https://doi.org/10.1089/can.2017.0047
Beck AT, Ward C, Mendelson M (1961) Beck depression inventory (BDI). Arch Gen Psychiatry 4:561–571
Bhattacharyya S et al (2012) Induction of psychosis by Δ9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Arch Gen Psychiatry 69:27–36. https://doi.org/10.1001/archgenpsychiatry.2011.161
Bhattacharyya S, Crippa JA, Martin-Santos R, Winton-Brown T, Fusar-Poli P (2009) Imaging the neural effects of cannabinoids: current status and future opportunities for psychopharmacology. Curr Pharm Des 15:2603–2614
Bhattacharyya S et al (2015) Cannabinoid modulation of functional connectivity within regions processing attentional salience. Neuropsychopharmacology 40:1343–1352. https://doi.org/10.1038/npp.2014.258
Bhattacharyya S et al (2010) Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35:764–774. https://doi.org/10.1038/npp.2009.184
Bloomfield MAP et al (2020) The effects of acute cannabidiol on cerebral blood flow and its relationship to memory: An arterial spin labelling magnetic resonance imaging study. J Psychopharmacol 34:981–989. https://doi.org/10.1177/0269881120936419
Bloomfield MAP et al (2019) The neuropsychopharmacology of cannabis: A review of human imaging studies. Pharmacol Ther 195:132–161. https://doi.org/10.1016/j.pharmthera.2018.10.006
Boggs DL et al (2018) The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology 235:1923–1932. https://doi.org/10.1007/s00213-018-4885-9
Borgwardt SJ et al (2008) Neural basis of Delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol Psychiatry 64:966–973. https://doi.org/10.1016/j.biopsych.2008.05.011
Bossong MG et al (2019) Association of Hippocampal Glutamate Levels With Adverse Outcomes in Individuals at Clinical High Risk for Psychosis. JAMA Psychiat 76:199–207. https://doi.org/10.1001/jamapsychiatry.2018.3252
Bowdle AT, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP (1998) Psychedelic effects of ketamine in healthy volunteers relationship to steady-state plasma concentrations. Anesthesiology 88:82–88. https://doi.org/10.1097/00000542-199801000-00015
Broyd SJ et al. (2016a) Mismatch negativity and P50 sensory gating in abstinent former cannabis users. Neural Plast 2016:11 https://doi.org/10.1155/2016/6526437
Broyd SJ, van Hell HH, Yucel M, Solowij N (2016b) Acute and chronic effects of cannabinoids on human cognition – a systematic review. Biol Psychiatry 79:557–567. https://doi.org/10.1016/j.biopsych.2015.12.002
Budney AJ, Hughes JR, Moore BA, Vandrey R (2004) Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry 161:1967–1977. https://doi.org/10.1176/appi.ajp.161.11.1967
Ceccarini J, Kuepper R, Kemels D, van Os J, Henquet C, Van Laere K (2015) [18F]MK-9470 PET measurement of cannabinoid CB1 receptor availability in chronic cannabis users. Addict Biol 20:357–367. https://doi.org/10.1111/adb.12116
Chung H, Fierro A, Pessoa-Mahana CD (2019) Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: An In Silico study. PLoS ONE 14:e0220025–e0220025. https://doi.org/10.1371/journal.pone.0220025
Chye Y et al (2019) Alteration to hippocampal volume and shape confined to cannabis dependence: a multi-site study. Addict Biol 24:822–834. https://doi.org/10.1111/adb.12652
Colizzi M, Bhattacharyya S (2017) Does Cannabis Composition Matter? Differential Effects of Delta-9-tetrahydrocannabinol and Cannabidiol on Human Cognition. Curr Addict Rep 4:62–74. https://doi.org/10.1007/s40429-017-0142-2
Colizzi M et al (2015) Functional Genetic Variation of the Cannabinoid Receptor 1 and Cannabis Use Interact on Prefrontal Connectivity and Related Working Memory Behavior. Neuropsychopharmacology 40:640–649. https://doi.org/10.1038/npp.2014.213
Colizzi M, Murray R (2018) Cannabis and psychosis: what do we know and what should we do? Br J Psychiatry 212:195–196. https://doi.org/10.1192/bjp.2018.1
Colizzi M, Weltens N, McGuire P, Lythgoe D, Williams S, Van Oudenhove L, Bhattacharyya S (2020) Delta-9-tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis. Mol Psychiatry 25:3231–3240. https://doi.org/10.1038/s41380-019-0374-8
Crippa JA, Guimarães FS, Campos AC, Zuardi AW (2018) Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age. Front Immunol 9 https://doi.org/10.3389/fimmu.2018.02009
Croft RJ, Barry RJ (2000) EOG correction of blinks with saccade coefficients: a test and revision of the aligned-artefact average solution. Clin Neurophysiol 111:444–451. https://doi.org/10.1016/s1388-2457(99)00296-5
Davies C, Bhattacharyya S (2019) Cannabidiol as a potential treatment for psychosis. Ther Adv Psychopharmacol 9:2045125319881916. https://doi.org/10.1177/2045125319881916
Dawson DA, Grant BF, Stinson FS (2005) The AUDIT-C: screening for alcohol use disorders and risk drinking in the presence of other psychiatric disorders. Compr Psychiatry 46:405–416. https://doi.org/10.1016/j.comppsych.2005.01.006
de la Salle S et al (2019) Acute separate and combined effects of cannabinoid and nicotinic receptor agonists on MMN-indexed auditory deviance detection in healthy humans. Pharmacol Biochem Behav 184:172739. https://doi.org/10.1016/j.pbb.2019.172739
De Petrocellis L et al (2011) Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 163:1479–1494. https://doi.org/10.1111/j.1476-5381.2010.01166.x
Di Forti M et al (2015) Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. Lancet Psychiatry 2:233–238. https://doi.org/10.1016/S2215-0366(14)00117-5
Di Forti M et al (2019) The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study. The Lancet Psychiatry 6:427–436. https://doi.org/10.1016/S2215-0366(19)30048-3
Donaldson KR, Novak KD, Foti D, Marder M, Perlman G, Kotov R, Mohanty A (2020) Associations of mismatch negativity with psychotic symptoms and functioning transdiagnostically across psychotic disorders. J Abnorm Psychol 129:570–580. https://doi.org/10.1037/abn0000506
Erickson MA, Ruffle A, Gold JM (2016) A Meta-Analysis of Mismatch Negativity in Schizophrenia: From Clinical Risk to Disease Specificity and Progression. Biol Psychiatry 79:980–987. https://doi.org/10.1016/j.biopsych.2015.08.025
Fernández-Cabrera MR, Higuera-Matas A, Fernaud-Espinosa I, DeFelipe J, Ambrosio E, Miguel Miguéns (2018) Selective effects of Δ9-tetrahydrocannabinol on medium spiny neurons in the striatum. PLoS One 13 https://doi.org/10.1371/journal.pone.0200950
Figueiredo PR, Tolomeo S, Steele JD, Baldacchino A (2020) Neurocognitive consequences of chronic cannabis use: a systematic review and meta-analysis. Neurosci Biobehav Rev 108:358–369. https://doi.org/10.1016/j.neubiorev.2019.10.014
Fishbein M, Gov S, Assaf F, Gafni M, Keren O, Sarne Y (2012) Long-term behavioral and biochemical effects of an ultra-low dose of Δ9-tetrahydrocannabinol (THC): neuroprotection and ERK signaling. Exp Brain Res 221:437–448. https://doi.org/10.1007/s00221-012-3186-5
Fusar-Poli P et al (2009) Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry 66:95–105. https://doi.org/10.1001/archgenpsychiatry.2008.519
Goldenberg M, IsHak WW, Danovitch I (2017) Quality of life and recreational cannabis use. Am J Addict 26:8–25. https://doi.org/10.1111/ajad.12486
Gossop M, Marsden J, Stewart D (2002) Dual dependence: assessment of dependence upon alcohol and illicit drugs, and the relationship of alcohol dependence among drug misusers to patterns of drinking, illicit drug use and health problems. Addiction 97:169–178. https://doi.org/10.1046/j.1360-0443.2002.00028.x
Greenwood LM et al (2014) Chronic effects of cannabis use on the auditory mismatch negativity. Biol Psychiatry 75:449–458. https://doi.org/10.1016/j.biopsych.2013.05.035
Greenwood LM et al (2018) The effects of glycine on auditory mismatch negativity in schizophrenia. Schizophr Res 191:61–69. https://doi.org/10.1016/j.schres.2017.05.031
Grossberg S, Versace M (2008) Spikes, synchrony, and attentive learning by laminar thalamocortical circuits. Brain Res 1218:278–312. https://doi.org/10.1016/j.brainres.2008.04.024
Hall W, Degenhardt L (2014) The adverse health effects of chronic cannabis use. Drug Test Anal 6:39–45. https://doi.org/10.1002/dta.1506
Hall W, Hoch E, Lorenzetti V (2019) Cannabis use and mental health: risks and benefits. Eur Arch Psychiatry Clin Neurosci 269:1–3. https://doi.org/10.1007/s00406-019-00986-2
Hallak JE et al (2010) Performance of schizophrenic patients in the Stroop Color Word Test and electrodermal responsiveness after acute administration of cannabidiol (CBD). Braz J Psychiatry 32:56–61. https://doi.org/10.1590/s1516-44462010000100011
Harding IH et al (2012) Functional connectivity in brain networks underlying cognitive control in chronic cannabis users. Neuropsychopharmacology 37:1923–1933. https://doi.org/10.1038/npp.2012.39
Harms L, Parras GG, Michie PT, Malmierca MS (2020) The Role of Glutamate Neurotransmission in Mismatch Negativity (MMN), A Measure of Auditory Synaptic Plasticity and Change-detection. Neuroscience https://doi.org/10.1016/j.neuroscience.2020.01.046
Hirvonen J et al (2012a) Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry 17:642–649. https://doi.org/10.1038/mp.2011.82
Irby SM, Floyd RG (2013) Test Review: Wechsler Abbreviated Scale of Intelligence, Second Edition. Canadian Journal of School Psychology 28:295–299 https://doi.org/10.1177/0829573513493982
Jasper HH (1958) The ten-twenty electrode system of the International Federation. EEG Clinical Neurophysiology 10:371–375
Juckel G, Roser P, Nadulski T, Stadelmann AM, Gallinat J (2007) Acute effects of Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity. Schizophr Res 97:109–117. https://doi.org/10.1016/j.schres.2007.08.015
Kantrowitz JT (2019) N-methyl-d-aspartate-type glutamate receptor modulators and related medications for the enhancement of auditory system plasticity in schizophrenia. Schizophr Res 207:70–79. https://doi.org/10.1016/j.schres.2018.02.003
Kantrowitz JT et al (2018) Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms. Schizophr Res 191:70–79. https://doi.org/10.1016/j.schres.2017.02.027
Kaur M, Chitty KM, Lagopoulos J, Hickie IB, Duffy SL, Hermens DF (2019) Elucidating the glutamatergic processes underlying mismatch negativity deficits in early stage bipolar disorder and schizophrenia: A combined 1H-MRS and EEG study. J Psychiatr Res 113:83–89. https://doi.org/10.1016/j.jpsychires.2019.03.018
Kelley BG, Thayer SA (2004) Delta 9-tetrahydrocannabinol antagonizes endocannabinoid modulation of synaptic transmission between hippocampal neurons in culture. Neuropharmacology 46:709–715. https://doi.org/10.1016/j.neuropharm.2003.11.005
Kolb B, Li Y, Robinson T, Parker LA (2018) THC alters alters morphology of neurons in medial prefrontal cortex, orbital prefrontal cortex, and nucleus accumbens and alters the ability of later experience to promote structural plasticity. Synapse 72:e22020. https://doi.org/10.1002/syn.22020
Kujala T, Tervaniemi M, Schroger E (2007) The mismatch negativity in cognitive and clinical neuroscience: theoretical and methodological considerations. Biol Psychol 74:1–19. https://doi.org/10.1016/j.biopsycho.2006.06.001
Laprairie RB, Bagher AM, Kelly MEM, Dupré DJ, Denovan-Wright EM (2014) Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons. J Biol Chem 289:24845–24862. https://doi.org/10.1074/jbc.M114.557025
Lee JLC, Bertoglio LJ, Guimaraes FS, Stevenson CW (2017) Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. Br J Pharmacol 174:3242–3256. https://doi.org/10.1111/bph.13724
Leweke FM et al (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2:e94. https://doi.org/10.1038/tp.2012.15
Linares IM, Zuardi AW, Pereira LC, Queiroz RH, Mechoulam R, Guimarães FS, Crippa JA (2019) Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Braz J Psychiatry 41:9–14. https://doi.org/10.1590/1516-4446-2017-0015
Liu Z et al (2019) Model-based analysis on systemic availability of coadministered cannabinoids after controlled vaporised administration. Intern Med J N/a. https://doi.org/10.1111/imj.14415
Lorenzetti V, Chye Y, Silva P, Solowij N, Roberts CA (2019) Does regular cannabis use affect neuroanatomy? An updated systematic review and meta-analysis of structural neuroimaging studies. Eur Arch Psychiatry Clin Neurosci 269:59–71. https://doi.org/10.1007/s00406-019-00979-1
Lorenzetti V et al (2020) Neuroanatomical alterations in people with high and low cannabis dependence. Aust N Z J Psychiatry 54:68–75. https://doi.org/10.1177/0004867419859077
Lorenzetti V, Cousijn J, Solowij N, Garavan H, Suo C, Yücel M, Verdejo-García A (2016a) The Neurobiology of Cannabis Use Disorders: A Call for Evidence. Front Behav Neurosci 10 https://doi.org/10.3389/fnbeh.2016.00086
Lorenzetti V, Solowij N, Yücel M (2016b) The role of cannabinoids on neuroanatomical alterations in cannabis users. Biol Psychiatry 79:17–31
Martin-Santos R et al (2012) Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des 18:4966–4979
Mato S, Chevaleyre V, Robbe D, Pazos A, Castillo PE, Manzoni OJ (2004) A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity. Nat Neurosci 7:585–586. https://doi.org/10.1038/nn1251
McPartland JM, Duncan M, Di Marzo V, Pertwee RG (2015) Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A Systematic Review Br J Pharmacol 172(737–753):7. https://doi.org/10.1111/bph.12944
McQuail JA, Frazier CJ, Bizon JL (2015) Molecular aspects of age-related cognitive decline: the role of GABA signaling. Trends Mol Med 21:450–460. https://doi.org/10.1016/j.molmed.2015.05.002
Millar SA, Stone NL, Yates AS, O’Sullivan SE (2018) A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front Pharmacol 9:1365. https://doi.org/10.3389/fphar.2018.01365
Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370:319–328. https://doi.org/10.1016/S0140-6736(07)61162-3
Morrison PD, Murray RM (2020) Cannabis points to the synaptic pathology of mental disorders: how aberrant synaptic components disrupt the highest psychological functions. Dialogues Clin Neurosci 22:251–258. https://doi.org/10.31887/DCNS.2020.22.3/pmorrison
Muetzel RL et al (2013) In vivo 1H magnetic resonance spectroscopy in young-adult daily marijuana users. NeuroImage: Clinical 2:581–589. https://doi.org/10.1016/j.nicl.2013.04.011
Murphy M, Mills S, Winstone J, Leishman E, Wager-Miller J, Bradshaw H, Mackie K (2017) Chronic Adolescent Δ(9)-Tetrahydrocannabinol Treatment of Male Mice Leads to Long-Term Cognitive and Behavioral Dysfunction, Which Are Prevented by Concurrent Cannabidiol Treatment. Cannabis and Cannabinoid Research 2:235–246. https://doi.org/10.1089/can.2017.0034
Murray RM et al (2017) Cannabis-associated psychosis: Neural substrate and clinical impact. Neuropharmacology 124:89–104. https://doi.org/10.1016/j.neuropharm.2017.06.018
Näätänen R, Shiga T, Asano S, Yabe H (2015) Mismatch negativity (MMN) deficiency: a break-through biomarker in predicting psychosis onset. Int J Psychophysiol 95:338–344. https://doi.org/10.1016/j.ijpsycho.2014.12.012
Navarrete M et al (2019) Astrocytic p38α MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory. Nat Commun 10:2968. https://doi.org/10.1038/s41467-019-10830-9
Niesink RJ, Rigter S, Koeter MW, Brunt TM (2015) Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005–15. Addiction 110:1941–1950
Niesink RJ, van Laar MW (2013) Does Cannabidiol Protect Against Adverse Psychological Effects of THC? Front Psychiatry 4:130. https://doi.org/10.3389/fpsyt.2013.00130
Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113
Osborne AL, Solowij N, Weston-Green K (2017) A systematic review of the effect of cannabidiol on cognitive function: Relevance to schizophrenia. Neurosci Biobehav Rev 72:310–324. https://doi.org/10.1016/j.neubiorev.2016.11.012
Paronis CA, Nikas SP, Shukla VG, Makriyannis A (2012) Δ(9)-Tetrahydrocannabinol acts as a partial agonist/antagonist in mice. Behav Pharmacol 23:802–805. https://doi.org/10.1097/FBP.0b013e32835a7c4d
Parsons LH, Hurd YL (2015) Endocannabinoid signaling in reward and addiction. Nat Rev Neurosci 16:579–594. https://doi.org/10.1038/nrn4004
Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Delta(9)-tetrahydrocannabinol, cannabidiol and Delta(9)-tetrahydrocannabivarin. Br J Pharmacol 153:199–215. https://doi.org/10.1038/sj.bjp.0707442
Pesa N, Hermens DF, Battisti RA, Kaur M, Hickie IB, Solowij N (2012) Delayed preattentional functioning in early psychosis patients with cannabis use. Psychopharmacology 222:507–518. https://doi.org/10.1007/s00213-012-2676-2
Plitman E et al (2014) Glutamate-mediated excitotoxicity in schizophrenia: a review. Eur Neuropsychopharmacol 24:1591–1605. https://doi.org/10.1016/j.euroneuro.2014.07.015
Prescot AP, Renshaw PF, Yurgelun-Todd DA (2013) γ-Amino butyric acid and glutamate abnormalities in adolescent chronic marijuana smokers. Drug Alcohol Depend 129:232–239. https://doi.org/10.1016/j.drugalcdep.2013.02.028
Pretzsch CM et al (2019) 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 44:1398–1405. https://doi.org/10.1038/s41386-019-0333-8
Raine A (1991) The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria. Schizophr Bull 17:555. https://doi.org/10.1093/schbul/17.4.555
Rentzsch J, Buntebart E, Stadelmeier A, Gallinat J, Jockers-Scherubl MC (2011) Differential effects of chronic cannabis use on preattentional cognitive functioning in abstinent schizophrenic patients and healthy subjects. Schizophr Res 130:222–227. https://doi.org/10.1016/j.schres.2011.05.011
Roser P, Della B, Norra C, Uhl I, Brune M, Juckel G (2010) Auditory mismatch negativity deficits in long-term heavy cannabis users. Eur Arch Psychiatry Clin Neurosci 260:491–498. https://doi.org/10.1007/s00406-010-0097-y
Sheehan DV et al. (1998) 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 59 Suppl 20:22–33;quiz 34–57
Sobell LC, Sobell MB (1992) Timeline Follow-Back. In: Litten RZ, Allen JP (eds) Measuring Alcohol Consumption: Psychosocial and Biochemical Methods. Humana Press, Totowa, NJ, pp 41–72. https://doi.org/10.1007/978-1-4612-0357-5-3
Solowij N (2012) Vulnerability markers in the association between cannabis and schizophrenia: a randomised controlled trial of acute cannabinoid administration. ISRCTN
Solowij N et al (2019) A randomised controlled trial of vaporised Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects. Eur Arch Psychiatry Clin Neurosci 269:17–35. https://doi.org/10.1007/s00406-019-00978-2
Solowij N, Broyd SJ, van Hell HH, Hazekamp A (2014) A protocol for the delivery of cannabidiol (CBD) and combined CBD and 9-tetrahydrocannabinol (THC) by vaporisation. BMC Pharmacol Toxicol 15:58. https://doi.org/10.1186/2050-6511-15-58
Solowij N, Michie PT (2007) Cannabis and cognitive dysfunction: Parallels with endophenotypes of schizophrenia? J Psychiatry Neurosci 32:30–52 (PMID:17245472)
Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA (1983) Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press, Palo Alto, CA
Stefanis N et al (2002) Evidence that three dimensions of psychosis have a distribution in the general population. Psychol Med 32:347–358. https://doi.org/10.1017/s0033291701005141
Straiker A, Dvorakova M, Zimmowitch A, Mackie K (2018) Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons. Mol Pharmacol 94:743. https://doi.org/10.1124/mol.118.111864
Tham M, Yilmaz O, Alaverdashvili M, Kelly MEM, Denovan-Wright EM, Laprairie RB (2019) Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol 176:1455–1469. https://doi.org/10.1111/bph.14440
Turner SE, Williams CM, Iversen L, Whalley BJ (2017) Molecular Pharmacology of Phytocannabinoids. In: Kinghorn AD, Falk H, Gibbons S, Kobayashi Ji (eds) Phytocannabinoids: Unraveling the Complex Chemistry and Pharmacology of Cannabis sativa. Springer International Publishing, Cham, pp 61–101. https://doi.org/10.1007/978-3-319-45541-9_3
Umbricht D, Krljes S (2005) Mismatch negativity in schizophrenia: a meta-analysis. Schizophr Res 76:1–23. https://doi.org/10.1016/j.schres.2004.12.002
United Nations Office on Drugs and Crime (2020) World Drug Report. United Nations, New York
van der Steur SJ, Batalla A, Bossong MG (2020) Factors Moderating the Association between Cannabis Use and Psychosis Risk: A Systematic Review. Brain Sci 10:97. https://doi.org/10.3390/brainsci10020097
Winton-Brown TT et al (2011) Modulation of auditory and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: an FMRI study. Neuropsychopharmacology 36:1340–1348. https://doi.org/10.1038/npp.2011.17
Yücel M et al (2016) Hippocampal harms, protection and recovery following regular cannabis use. Transl Psychiatry 6:e710. https://doi.org/10.1038/tp.2015.201
Zamberletti E et al (2016) Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats. Pharmacol Res 111:459–470. https://doi.org/10.1016/j.phrs.2016.07.008
Zuardi AW, Rodrigues NP, Silva AL, Bernardo SA, Hallak JEC, Guimarães FS, Crippa JAS (2017) Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life. Front Pharmacol 8 https://doi.org/10.3389/fphar.2017.00259
Acknowledgements
The authors are grateful to (1) Professor Antonio Zuardi and Dr Arno Hazekamp for advice around dosing and drug administration at the commencement of the study and (2) to Storz & Bickel, Tuttlingen, Germany, for supplying a Volcano® Vaporiser used in this study. Cannabinoid compounds were purchased from STI Pharmaceuticals, UK. The authors are grateful to Clare Bate, Camilla Beale, Andrew Bonney, Gary Chan, Francesca Fernandez, Sarah Gallagher, David Garne, Madeleine Godber, Stuart Johnstone, Lisa Lole, Elke Macdonald, David Martelozzo, Philip McGuire, Jelena Novakovic, Nagesh Pai, Gabrielle Puckett, Karina Rovere, Kuna Rueb, Beth Shaw and Lara Tramazzo for assistance with participant, trial and data management and logistics.
Funding
This research was supported by the National Health and Medical Research Council of Australia (NHMRC Project grant 1007593). NS was supported by the Australian Research Council (ARC Future Fellowship FT110100752) and LMG was supported by a National Institutes Grant (NIG). Neither the NHMRC, ARC nor the Australian Government had any further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
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Greenwood, LM., Broyd, S.J., van Hell, H.H. et al. Acute effects of Δ9-tetrahydrocannabinol and cannabidiol on auditory mismatch negativity. Psychopharmacology 239, 1409–1424 (2022). https://doi.org/10.1007/s00213-021-05997-3
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DOI: https://doi.org/10.1007/s00213-021-05997-3