Does Cannabis Composition Matter? Differential Effects of Delta-9-tetrahydrocannabinol and Cannabidiol on Human Cognition

Current Addiction Reports

Volumn 4, Issue 2, 2017, Pages 62-74

  Colizzi, Marco ^a   Bhattacharyya, Sagnik ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Brain function; Cannabidiol; Cannabis; Cognitive processing; Delta 9 tetrahydrocannabinol

Indexed keywords

EID: 85041132475     PISSN: None     EISSN: 21962952     Source Type: Journal    
DOI: 10.1007/s40429-017-0142-2     Document Type: Review

References (84)

1. United Nations Office on Drugs and Crime. World drug report 2016. United Nations publication. Sales No. E.16.XI.7.
2. Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370(9584):319–28.
3. Murray RM, Morrison PD, Henquet C, Di Forti M. Cannabis, the mind and society: the hash realities. Nat Rev Neurosci. 2007;8(11):885–95.
4. Schoeler T, Petros N, Di Forti M, Pingault JB, Klamerus E, Foglia E, et al. Association between continued cannabis use and risk of relapse in first-episode psychosis: a quasi-experimental investigation within an observational study. JAMA Psychiatry. 2016;73(11):1173–9.
5. Schoeler T, Petros N, Di Forti M, Klamerus E, Foglia E, Ajnakina O, et al. Effects of continuation, frequency, and type of cannabis use on relapse in the first 2 years after onset of psychosis: an observational study. Lancet Psychiatry. 2016;3(10):947–53.
6. Schoeler T, Monk A, Sami MB, Klamerus E, Foglia E, Brown R, et al. Continued versus discontinued cannabis use in patients with psychosis: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3(3):215–25.
7. Patel R, Wilson R, Jackson R, Ball M, Shetty H, Broadbent M, et al. Association of cannabis use with hospital admission and antipsychotic treatment failure in first episode psychosis: an observational study. BMJ Open. 2016;6(3):e009888.
8. Colizzi M, Carra E, Fraietta S, Lally J, Quattrone D, Bonaccorso S, et al. Substance use, medication adherence and outcome one year following a first episode of psychosis. Schizophr Res. 2016;170(2–3):311–7.
9. D'Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu YT, et al. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology. 2004;29(8):1558–72.
10. Bhattacharyya S, Atakan Z, Martin-Santos R, Crippa JA, Kambeitz J, Prata D, et al. Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of delta-9-tetrahydrocannabinol on midbrain and striatal function. Mol Psychiatry. 2012;17(12):1152–5.
11. Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martin-Santos R, Nosarti C, O’Carroll C, et al. 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.
12. Appiah-Kusi E, Leyden E, Parmar S, Mondelli V, McGuire P, Bhattacharyya S. Abnormalities in neuroendocrine stress response in psychosis: the role of endocannabinoids. Psychol Med. 2016;46(1):27–45.
13. Owen M, Sawa A, Mortensen P. Schizophrenia. Lancet. 2016;388(10039):86–97.
14. Bolla KI, Brown K, Eldreth D, Tate K, Cadet JL. Dose-related neurocognitive effects of marijuana use. Neurology. 2002;59(9):1337–43.
15. Jockers-Scherubl MC, Wolf T, Radzei N, Schlattmann P, Rentzsch J, Gomez-Carrillo de Castro A, et al. Cannabis induces different cognitive changes in schizophrenic patients and in healthy controls. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31(5):1054–63.
16. Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, et al. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA. 2002;287(9):1123–31.
17. Schoeler T, Kambeitz J, Behlke I, Murray R, Bhattacharyya S. The effects of cannabis on memory function in users with and without a psychotic disorder: findings from a combined meta-analysis. Psychol Med. 2016;46(1):177–88.
18. Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D. Neuropsychological performance in long-term cannabis users. Arch Gen Psychiatry. 2001;58(10):909–15.
19. Mata I, Rodriguez-Sanchez JM, Pelayo-Teran JM, Perez-Iglesias R, Gonzalez-Blanch C, Ramirez-Bonilla M, et al. Cannabis abuse is associated with decision-making impairment among first-episode patients with schizophrenia-spectrum psychosis. Psychol Med. 2008;38(9):1257–66.
20. Schnell T, Koethe D, Daumann J, Gouzoulis-Mayfrank E. The role of cannabis in cognitive functioning of patients with schizophrenia. Psychopharmacology. 2009;205(1):45–52.
21. Sevy S, Burdick KE, Visweswaraiah H, Abdelmessih S, Lukin M, Yechiam E, et al. Iowa gambling task in schizophrenia: a review and new data in patients with schizophrenia and co-occurring cannabis use disorders. Schizophr Res. 2007;92(1–3):74–84.
22. Ruiz-Contreras AE, Carrillo-Sanchez K, Gomez-Lopez N, Vadillo-Ortega F, Hernandez-Morales S, Carnevale-Cantoni A, et al. Working memory performance in young adults is associated to the AATn polymorphism of the CNR1 gene. Behav Brain Res. 2013;236(1):62–6.
23. Ruiz-Contreras AE, Carrillo-Sanchez K, Ortega-Mora I, Barrera-Tlapa MA, Roman-Lopez TV, Rosas-Escobar CB, et al. Performance in working memory and attentional control is associated with the rs2180619 SNP in the CNR1 gene. Genes Brain Behav. 2014;13(2):173–8.
24. Colizzi M, Fazio L, Ferranti L, Porcelli A, Masellis R, Marvulli D, et al. Functional genetic variation of the cannabinoid receptor 1 and cannabis use interact on prefrontal connectivity and related working memory behavior. Neuropsychopharmacology. 2015;40(3):640–9.
25. Taurisano P, Antonucci LA, Fazio L, Rampino A, Romano R, Porcelli A, et al. Prefrontal activity during working memory is modulated by the interaction of variation in CB1 and COX2 coding genes and correlates with frequency of cannabis use. Cortex. 2016;81:231–8.
26. Bhattacharyya S, Atakan Z, Martin-Santos R, Crippa JA, Kambeitz J, Prata D, et al. Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of delta-9-tetrahydrocannabinol on midbrain and striatal function. Mol. Psychiatry. 2012;17:1152–5.
27. van Winkel R, van Beveren NJ, Simons C, Genetic R. Outcome of psychosis I. AKT1 moderation of cannabis-induced cognitive alterations in psychotic disorder. Neuropsychopharmacology. 2011;36(12):2529–37.
28. Colizzi M, Iyegbe C, Powell J, Ursini G, Porcelli A, Bonvino A, et al. Interaction between functional genetic variation of DRD2 and cannabis use on risk of psychosis. Schizophr Bull. 2015;41(5):1171–82.
29. Bhattacharyya S, Iyegbe C, Atakan Z, Martin-Santos R, Crippa JA, Xu X, et al. Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control. Psychol Med. 2014;44(15):3315–28.
30. Grant I, Gonzalez R, Carey CL, Natarajan L, Wolfson T. Non-acute (residual) neurocognitive effects of cannabis use: a meta-analytic study. J Int Neuropsychol Soc. 2003;9(5):679–89.
31. Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012;109(40):E2657–64.
32. Jager G, Block RI, Luijten M, Ramsey NF. Cannabis use and memory brain function in adolescent boys: a cross-sectional multicenter functional magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry. 2010;49(6):561–72. 72 e1–3
33. Jager G, Van Hell HH, De Win MM, Kahn RS, Van Den Brink W, Van Ree JM, et al. Effects of frequent cannabis use on hippocampal activity during an associative memory task. Eur Neuropsychopharmacol. 2007;17(4):289–97.
34. Bossong MG, Jager G, van Hell HH, Zuurman L, Jansma JM, Mehta MA, et al. Effects of delta9-tetrahydrocannabinol administration on human encoding and recall memory function: a pharmacological FMRI study. J Cogn Neurosci. 2012;24(3):588–99.
35. Bossong MG, Jager G, Bhattacharyya S, Allen P. Acute and non-acute effects of cannabis on human memory function: a critical review of neuroimaging studies. Curr Pharm Des. 2014;20(13):2114–25.
36. Mechoulam R, Gaoni Y. Recent advances in the chemistry of hashish. Fortschritte der Chemie organischer Naturstoffe Progress in the chemistry of organic natural products. 1967;25:175–213.
37. Mechoulam R, Shani A, Edery H, Grunfeld Y. Chemical basis of hashish activity. Science. 1970;169(3945):611–2.
38. Niesink RJ, van Laar MW. Does cannabidiol protect against adverse psychological effects of THC? Front Psychiatry. 2013;4:130.
39. Radhakrishnan R, Wilkinson ST, D'Souza DC. Gone to pot—a review of the association between cannabis and psychosis. Front Psychiatry. 2014;5:54.
40. Colizzi M, McGuire P, Pertwee RG, Bhattacharyya S. Effect of cannabis on glutamate signalling in the brain: a systematic review of human and animal evidence. Neurosci Biobehav Rev. 2016;64:359–81.
41. Bhattacharyya S, Atakan Z, Martin-Santos R, Crippa JA, McGuire PK. Neural mechanisms for the cannabinoid modulation of cognition and affect in man: a critical review of neuroimaging studies. Curr Pharm Des. 2012;18(32):5045–54.
42. Di Forti M, Marconi A, Carra E, Fraietta S, Trotta A, Bonomo M, et al. Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. Lancet Psychiatry. 2015;2(3):233–8.
43. Zamberletti E, Beggiato S, Steardo L Jr, Prini P, Antonelli T, Ferraro L, et al. Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats. Neurobiol Dis. 2014;63:35–47.
44. Campolongo P, Trezza V, Cassano T, Gaetani S, Morgese MG, Ubaldi M, et al. Perinatal exposure to delta-9-tetrahydrocannabinol causes enduring cognitive deficits associated with alteration of cortical gene expression and neurotransmission in rats. Addict Biol. 2007;12(3–4):485–95.
45. Ranganathan M, D’Souza DC. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology. 2006;188(4):425–44.
46. Hall W, Solowij N. Adverse effects of cannabis. Lancet. 1998;352(9140):1611–6.
47. Curran HV, Brignell C, Fletcher S, Middleton P, Henry J. Cognitive and subjective dose-response effects of acute oral delta 9-tetrahydrocannabinol (THC) in infrequent cannabis users. Psychopharmacology. 2002;164(1):61–70.
48. D'Souza DC, Ranganathan M, Braley G, Gueorguieva R, Zimolo Z, Cooper T, et al. Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology. 2008;33(10):2505–16.
49. Batalla A, Crippa JA, Busatto GF, Guimaraes FS, Zuardi AW, Valverde O, et al. Neuroimaging studies of acute effects of THC and CBD in humans and animals: a systematic review. Curr Pharm Des. 2014;20(13):2168–85.
50. Morgan CJ, Gardener C, Schafer G, Swan S, Demarchi C, Freeman TP, et al. Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being. Psychol Med. 2012;42(2):391–400.
51. Morgan CJ, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study: naturalistic study [corrected]. Br J Psychiatry. 2010;197(4):285–90.
52. •• Englund A, Morrison PD, Nottage J, Hague D, Kane F, Bonaccorso S, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol. 2013;27(1):19–27. Compared to CBD pretreatment, placebo pretreatment is associated with a poorer verbal memory performance following Δ9-THC administration. Δ9-THC administration affects working memory performance following pretreatment with placebo, while pretreatment with CBD is able to partially prevent the detrimental effects of Δ9-THC on working memory.
53. •• Hindocha C, Freeman TP, Schafer G, Gardener C, Das RK, Morgan CJ, et al. Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users. Eur Neuropsychopharmacol. 2015;25(3):325–34. Administration of Δ9-THC alone has a detrimental effect on emotional processing accuracy. This effect is no longer present is Δ9-THC is administered in combination with CBD. Administration of CBD alone is associated with higher emotional processing accuracy compared to placebo.
54. Roser P, Juckel G, Rentzsch J, Nadulski T, Gallinat J, Stadelmann AM. Effects of acute oral delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers. Eur Neuropsychopharmacol. 2008;18(8):569–77.
55. Schoedel KA, Chen N, Hilliard A, White L, Stott C, Russo E, et al. A randomized, double-blind, placebo-controlled, crossover study to evaluate the subjective abuse potential and cognitive effects of nabiximols oromucosal spray in subjects with a history of recreational cannabis use. Hum Psychopharmacol. 2011;26(3):224–36.
56. Gruber SA, Sagar KA, Dahlgren MK, Racine MT, Smith RT, Lukas SE. Splendor in the grass? A pilot study assessing the impact of medical marijuana on executive function. Front Pharmacol. 2016;7:355.
57. Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003;17(1):21–9.
58. •• Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35(3):764–74. Δ9-THC and CBD have opposite effects on neural networks underlying several cognitive processes, including verbal memory, emotional processing, executive function, and visual and auditory processing. Some of these effects correlate with the harmful (e.g., Δ9-THC-induced psychotic or anxiety symptoms) or beneficial (e.g., anxiolytic effect of CBD) effects of these cannabinoids on behavior.
59. Winton-Brown TT, Allen P, Bhattacharyya S, Borgwardt SJ, Fusar-Poli P, Crippa JA, et al. Modulation of auditory and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: an FMRI study. Neuropsychopharmacology. 2011;36(7):1340–8.
60. Bhattacharyya S, Crippa JA, Allen P, Martin-Santos R, Borgwardt S, Fusar-Poli P, et al. Induction of psychosis by delta9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Arch Gen Psychiatry. 2012;69(1):27–36.
61. •• Bhattacharyya S, Falkenberg I, Martin-Santos R, Atakan Z, Crippa JA, Giampietro V, et al. Cannabinoid modulation of functional connectivity within regions processing attentional salience. Neuropsychopharmacology. 2015;40(6):1343–52. Δ9-THC and CBD have opposite effects on functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Mediotemporal-prefrontal connectivity is enhanced under the Δ9-THC condition, but reduced following CBD administration. Fronto-striatal connectivity is enhanced by CBD, but reduced under Δ9-THC. Effect of Δ9-THC on fronto-striatal connectivity correlates with response latency while performing the task.
62. Englund A, Atakan Z, Kralj A, Tunstall N, Murray R, Morrison P. The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: a placebo-controlled, double-blind, crossover pilot trial. J Psychopharmacol. 2016;30(2):140–51.
63. Hallak JE, Machado-de-Sousa JP, Crippa JA, Sanches RF, Trzesniak C, Chaves C, et al. Performance of schizophrenic patients in the Stroop Color Word Test and electrodermal responsiveness after acute administration of cannabidiol (CBD). Rev Bras Psiquiatr. 2010;32(1):56–61.
64. Potter DJ, Clark P, Brown MB. Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci. 2008;53(1):90–4.
65. ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in cannabis potency over the last 2 decades (1995–2014): analysis of current data in the United States. Biol Psychiatry. 2016;79(7):613–9.
66. Swift W, Wong A, Li KM, Arnold JC, McGregor IS. Analysis of cannabis seizures in NSW, Australia: cannabis potency and cannabinoid profile. PLoS One. 2013;8(7):e70052.
67. Cascini F, Aiello C, Di Tanna G. Increasing delta-9-tetrahydrocannabinol (delta-9-THC) content in herbal cannabis over time: systematic review and meta-analysis. Curr Drug Abuse Rev. 2012;5(1):32–40.
68. Pope HG Jr, Yurgelun-Todd D. The residual cognitive effects of heavy marijuana use in college students. JAMA. 1996;275(7):521–7.
69. Pope HG Jr. Cannabis, cognition, and residual confounding. JAMA. 2002;287(9):1172–4.
70. Eldreth DA, Matochik JA, Cadet JL, Bolla KI. Abnormal brain activity in prefrontal brain regions in abstinent marijuana users. NeuroImage. 2004;23(3):914–20.
71. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199–215.
72. Zuardi AW, Karniol IG. Effects on variable-interval performance in rats of delta 9-tetrahydrocannabinol and cannabidiol, separately and in combination. Braz J Med Biol Res. 1983;16(2):141–6.
73. Musty RE, Sands R. Effects of marijuana extract distillate and cannabidiol on variable interval performance as a function of food deprivation. Pharmacology. 1978;16(4):199–205.
74. Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology. 1990;100(4):558–9.
75. Onaivi ES, Green MR, Martin BR. Pharmacological characterization of cannabinoids in the elevated plus maze. J Pharmacol Exp Ther. 1990;253(3):1002–9.
76. Guimaraes FS, de Aguiar JC, Mechoulam R, Breuer A. Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze. Gen Pharmacol. 1994;25(1):161–4.
77. Zuardi AW, Cosme RA, Graeff FG, Guimaraes FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol. 1993;7(1 Suppl):82–8.
78. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology. 1982;76(3):245–50.
79. Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25(1):121–30.
80. Osborne AL, Solowij N, Weston-Green K. A systematic review of the effect of cannabidiol on cognitive function: relevance to schizophrenia. Neurosci Biobehav Rev. 2016;72:310–24.
81. Colizzi M, Iyegbe C, Powell J, Blasi G, Bertolino A, Murray RM, et al. Interaction between DRD2 and AKT1 genetic variations on risk of psychosis in cannabis users: a case-control study. NPJ Schizophr. 2015;1:15025.
82. Bhattacharyya S, Atakan Z, Martin-Santos R, Crippa JA, Kambeitz J, Malhi S, et al. Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis. Eur Neuropsychopharmacol. 2015;25(1):26–37.
83. Schoeler T, Theobald D, Pingault JB, Farrington DP, Jennings WG, Piquero AR, et al. Continuity of cannabis use and violent offending over the life course. Psychol Med. 2016;46(8):1663–77.
84. Velayudhan L, Van Diepen E, Marudkar M, Hands O, Suribhatla S, Prettyman R, et al. Therapeutic potential of cannabinoids in neurodegenerative disorders: a selective review. Curr Pharm Des. 2014;20(13):2218–30.