The effects of Δ9-tetrahydrocannabinol on the dopamine system


The effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid–dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC.

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Figure 1: THC binds to CB1 receptors on glutamatergic and GABAergic neurons, disrupting normal endocannabinoid retrograde signalling from dopaminergic neurons135.
Figure 2: Summary of the acute effects of THC on dopaminergic function.
Figure 3: Cannabis use in humans is associated with reduced dopamine in the striatum. PET studies have shown lower striatal dopamine synthesis and release capacity in cannabis users.


  1. 1

    Substance Abuse and Mental Health Services Administration. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings Vol. HHS Publication No. (SMA) 14–4863 (Substance Abuse and Mental Health Services Administration, 2014)

  2. 2

    EMCDDA. European Drug Report 2015: Trends and Developments (European Monitoring Centre for Drugs and Drug Addiction, Lisbon, 2015)

  3. 3

    Volkow, N. D. et al. Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA Psychiatry 73, 292–297 (2016)

    Google Scholar 

  4. 4

    Di Forti, M. et al. Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users. Schizophr. Bull. 40, 1509–1517 (2014)

    Google Scholar 

  5. 5

    Fergusson, D. M., Boden, J. M. & Horwood, L. J. Cannabis use and other illicit drug use: testing the cannabis gateway hypothesis. Addiction 101, 556–569 (2006)

    Google Scholar 

  6. 6

    Horwood, L. J. et al. Cannabis and depression: an integrative data analysis of four Australasian cohorts. Drug Alcohol Depend. 126, 369–378 (2012)

    Google Scholar 

  7. 7

    Silins, E. et al. Young adult sequelae of adolescent cannabis use: an integrative analysis. Lancet Psychiatry 1, 286–293 (2014)

    Google Scholar 

  8. 8

    Crane, N. A., Schuster, R. M., Fusar-Poli, P. & Gonzalez, R. Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences, and sex differences. Neuropsychol. Rev. 23, 117–137 (2013)

    Google Scholar 

  9. 9

    Cherek, D. R., Lane, S. D. & Dougherty, D. M. Possible amotivational effects following marijuana smoking under laboratory conditions. Exp. Clin. Psychopharmacol. 10, 26–38 (2002)

    Google Scholar 

  10. 10

    Wachtel, S. R., ElSohly, M. A., Ross, S. A., Ambre, J. & de Wit, H. Comparison of the subjective effects of Δ9-tetrahydrocannabinol and marijuana in humans. Psychopharmacology (Berl.) 161, 331–339 (2002)

    CAS  Google Scholar 

  11. 11

    Felder, C. C., Veluz, J. S., Williams, H. L., Briley, E. M. & Matsuda, L. A. Cannabinoid agonists stimulate both receptor- and non-receptor-mediated signal transduction pathways in cells transfected with and expressing cannabinoid receptor clones. Mol. Pharmacol. 42, 838–845 (1992)

    CAS  Google Scholar 

  12. 12

    Mehmedic, Z. et al. Potency trends of Δ9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J. Forensic Sci. 55, 1209–1217 (2010)

    CAS  Google Scholar 

  13. 13

    Spaderna, M., Addy, P. H. & D’Souza, D. C. Spicing things up: synthetic cannabinoids. Psychopharmacology (Berl.) 228, 525–540 (2013)

    CAS  Google Scholar 

  14. 14

    Benjamin, D. M. & Fossler, M. J. Edible cannabis products: it is time for FDA oversight. J. Clin. Pharmacol. (2016)

  15. 15

    Varlet, V. et al. Drug vaping applied to cannabis: Is “Cannavaping” a therapeutic alternative to marijuana? Sci. Rep. 6, 25599 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Vallee, M. et al. Pregnenolone can protect the brain from cannabis intoxication. Science 343, 94–98 (2014)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Huestis, M. A. et al. Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch. Gen. Psychiatry 58, 322–328 (2001).The psychoactive active effects of cannabis are mediated via the CB 1 receptor.

    CAS  Google Scholar 

  18. 18

    Elphick, M. R. & Egertova, M. The neurobiology and evolution of cannabinoid signalling. Phil. Trans. R. Soc. Lond. B 356, 381–408 (2001)

    CAS  Google Scholar 

  19. 19

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

    CAS  Google Scholar 

  20. 20

    Kathmann, M., Flau, K., Redmer, A., Trankle, C. & Schlicker, E. Cannabidiol is an allosteric modulator at μ- and δ-opioid receptors. Naunyn Schmiedebergs Arch. Pharmacol. 372, 354–361 (2006)

    CAS  Google Scholar 

  21. 21

    Chartoff, E. H. & Connery, H. S. It’s MORe exciting than mu: crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system. Front. Pharmacol. 5, 116 (2014)

    PubMed  PubMed Central  Google Scholar 

  22. 22

    Hollister, L. E. & Gillespie, H. K. Action of Δ9-tetrahydrocannabinol. An approach to the active metabolite hypothesis. Clin. Pharmacol. Ther. 18, 714–719 (1975)

    CAS  Google Scholar 

  23. 23

    Garriott, J. C., King, L. J., Forney, R. B. & Hughes, F. W. Effects of some tetrahydrocannabinols on hexobarbital sleeping time and amphetamine induced hyperactivity in mice. Life Sci. 6, 2119–2128 (1967)

    CAS  Google Scholar 

  24. 24

    Howes, J. & Osgood, P. The effect of Δ9-tetrahydrocannabinol on the uptake and release of 14C-dopamine from crude striatal synaptosoma; preparations. Neuropharmacology 13, 1109–1114 (1974)

    CAS  Google Scholar 

  25. 25

    Fernandez-Ruiz, J., Hernandez, M. & Ramos, J. A. Cannabinoid-dopamine interaction in the pathophysiology and treatment of CNS disorders. CNS Neurosci. Ther. 16, e72–e91 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Herkenham, M., Lynn, A. B., Decosta, B. R. & Richfield, E. K. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res. 547, 267–274 (1991)

    CAS  Google Scholar 

  27. 27

    Solinas, M., Justinova, Z., Goldberg, S. R. & Tanda, G. Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J. Neurochem. 98, 408–419 (2006)

    CAS  Google Scholar 

  28. 28

    De Luca, M. A. et al. Endocannabinoid 2-arachidonoylglycerol self-administration by Sprague–Dawley rats and stimulation of in vivo dopamine transmission in the nucleus accumbens shell. Front. Psychiatry 5, 140 (2014)

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Bloom, A. S. & Dewey, W. L. A comparison of some pharmacological actions of morphine and Δ9-tetrahydrocannabinol in the mouse. Psychopharmacology (Berl.) 57, 243–248 (1978)

    CAS  Google Scholar 

  30. 30

    Hershkowitz, M. & Szechtman, H. Pretreatment with Δ1-tetrahydrocannabinol and psychoactive drugs: effects on uptake of biogenic amines and on behavior. Eur. J. Pharmacol. 59, 267–276 (1979)

    CAS  Google Scholar 

  31. 31

    Poddar, M. K. & Dewey, W. L. Effects of cannabinoids on catecholamine uptake and release in hypothalamic and striatal synaptosomes. J. Pharmacol. Exp. Ther. 214, 63–67 (1980)

    CAS  Google Scholar 

  32. 32

    Aulakh, C. S., Bhattacharyya, A. K., Hossain, M. A. & Pradhan, S. N. Behavioral and neurochemical effects of repeated administration of Δ9-tetrahydrocannabinol in rats. Neuropharmacology 19, 97–102 (1980)

    CAS  Google Scholar 

  33. 33

    Maitre, L., Staehelin, M. & Bein, H. J. Effect of an extract of cannabis and of some cannabinols on catecholamine metabolism in rat brain and heart. Agents Actions 1, 136–143 (1970)

    CAS  Google Scholar 

  34. 34

    Bloom, A. S., Johnson, K. M. & Dewey, W. L. The effects of cannabinoids on body temperature and brain catecholamine synthesis. Res. Commun. Chem. Pathol. Pharmacol. 20, 51–57 (1978)

    CAS  Google Scholar 

  35. 35

    Romero, J., Demiguel, R., Garciapalomero, E., Fernandezruiz, J. J. & Ramos, J. A. Time-course of the effects of anandamide, the putative endogenous cannabinoid receptor-ligand, on extrapyramidal function. Brain Res. 694, 223–232 (1995)

    CAS  Google Scholar 

  36. 36

    Bosier, B. et al. Differential modulations of striatal tyrosine hydroxylase and dopamine metabolism by cannabinoid agonists as evidence for functional selectivity in vivo. Neuropharmacology 62, 2328–2336 (2012)

    CAS  Google Scholar 

  37. 37

    Navarro, M. et al. An acute dose of Δ9-tetrahydrocannabinol affects behavioral and neurochemical indices of mesolimbic dopaminergic activity. Behav. Brain Res. 57, 37–46 (1993)

    MathSciNet  CAS  Google Scholar 

  38. 38

    Heien, M. L. et al. Real-time measurement of dopamine fluctuations after cocaine in the brain of behaving rats. Proc. Natl Acad. Sci. USA 102, 10023–10028 (2005)

    ADS  CAS  Google Scholar 

  39. 39

    Pistis, M. et al. Δ9-Tetrahydrocannabinol decreases extracellular GABA and increases extracellular glutamate and dopamine levels in the rat prefrontal cortex: An in vivo microdialysis study. Brain Res. 948, 155–158 (2002)

    CAS  Google Scholar 

  40. 40

    Ng Cheong Ton, J. M. et al. The effects of Δ9-tetrahydrocannabinol on potassium-evoked release of dopamine in the rat caudate nucleus: an in vivo electrochemical and in vivo microdialysis study. Brain Res. 451, 59–68 (1988)

    CAS  Google Scholar 

  41. 41

    Chen, J. P. et al. Δ9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology (Berl.) 102, 156–162 (1990)

    CAS  Google Scholar 

  42. 42

    Castaneda, E., Moss, D., Oddie, S. & Whishaw, I. THC does not affect striatal dopamine release: Microdialysis in freely moving rats. Pharmacol. Biochem. Behav. 40, 587–591 (1991)

    CAS  Google Scholar 

  43. 43

    Nahas, G. G. in Medical Aspects of Drug Abuse (ed. R. W. Richter ) 16–36 (Harper & Row, 1975)

    Google Scholar 

  44. 44

    Chen, J., Paredes, W., Lowinson, J. & Gardner, E. Strain-specific facilitation of dopamine efflux by Δ9-tetrahydrocannabinol in the nucleus accumbens of rat: An in vivo microdialysis study. Neurosci. Lett. 129, 136–140 (1991)

    CAS  Google Scholar 

  45. 45

    Oleson, E. B. & Cheer, J. F. A brain on cannabinoids: the role of dopamine release in reward seeking. Cold Spring Harb. Perspect. Med. 2, a012229 (2012)

    PubMed  PubMed Central  Google Scholar 

  46. 46

    French, E. Δ9-Tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB1 but not opioid receptors. Neurosci. Lett. 226, 159–162 (1997)

    CAS  Google Scholar 

  47. 47

    Ali, S. F. et al. Chronic marijuana smoke exposure in the rhesus monkey. IV: Neurochemical effects and comparison to acute and chronic exposure to Δ9-tetrahydrocannabinol (THC) in rats. Pharmacol. Biochem. Behav. 40, 677–682 (1991)

    MathSciNet  CAS  Google Scholar 

  48. 48

    Navarro, M. et al. Motor disturbances induced by an acute dose of Δ9-tetrahydrocannabinol: Possible involvement of nigrostriatal dopaminergic alterations. Pharmacol. Biochem. Behav. 45, 291–298 (1993)

    CAS  Google Scholar 

  49. 49

    Rodríguez De Fonseca, F. et al. Acute effects of Δ9-tetrahydrocannabinol on dopaminergic activity in several rat-brain areas. Pharmacol. Biochem. Behav. 42, 269–275 (1992)

    Google Scholar 

  50. 50

    Volkow, N. D. et al. Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication. Psychiatry Res. 67, 29–38 (1996)

    CAS  Google Scholar 

  51. 51

    Pertwee, R. G. & Ross, R. A. Cannabinoid receptors and their ligands. Prostaglandins Leukot. Essent. Fatty Acids 66, 101–121 (2002)

    CAS  Google Scholar 

  52. 52

    Borgwardt, S. J. et al. Neural basis of Δ9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol. Psychiatry 64, 966–973 (2008)

    CAS  Google Scholar 

  53. 53

    Bhattacharyya, S. et al. Opposite effects of Δ9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35, 764–774 (2010)

    CAS  Google Scholar 

  54. 54

    van Hell, H. H. et al. Involvement of the endocannabinoid system in reward processing in the human brain. Psychopharmacology (Berl.) 219, 981–990 (2012)

    CAS  Google Scholar 

  55. 55

    Bossong, M. G. et al. Further human evidence for striatal dopamine release induced by administration of Δ9-tetrahydrocannabinol (THC): selectivity to limbic striatum. Psychopharmacology (Berl.) (2015)

  56. 56

    Stokes, P. R. et al. Significant decreases in frontal and temporal [11C]-raclopride binding after THC challenge. Neuroimage 52, 1521–1527 (2010)

    CAS  Google Scholar 

  57. 57

    Barkus, E. et al. Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study. J. Psychopharmacol. 25, 1462–1468 (2011)

    CAS  Google Scholar 

  58. 58

    Volkow, N. D. et al. Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D2 receptors. J. Pharmacol. Exp. Ther. 291, 409–415 (1999)

    CAS  Google Scholar 

  59. 59

    Egerton, A., Demjaha, A., McGuire, P., Mehta, M. A. & Howes, O. D. The test-retest reliability of 18F-DOPA PET in assessing striatal and extrastriatal presynaptic dopaminergic function. Neuroimage 50, 524–531 (2010)

    Google Scholar 

  60. 60

    Jentsch, J., Verrico, C., Le, D. & Roth, R. Repeated exposure to Δ9-tetrahydrocannabinol reduces prefrontal cortical dopamine metabolism in the rat. Neurosci. Lett. 246, 169–172 (1998)

    CAS  Google Scholar 

  61. 61

    Avraham, Y. et al. Very low doses of Δ8-THC increase food consumption and alter neurotransmitter levels following weight loss. Pharmacol. Biochem. Behav. 77, 675–684 (2004)

    CAS  Google Scholar 

  62. 62

    Jentsch, J., Andrusiak, E., Tran, A., Bowers, Jr. & Roth, R. Δ9-Tetrahydrocannabinol increases prefrontal cortical catecholaminergic utilization and impairs spatial working memory in the rat: Blockade of dopaminergic effects with HA966. Neuropsychopharmacology 16, 426–432 (1997)

    CAS  Google Scholar 

  63. 63

    Ginovart, N. et al. Chronic Δ9-tetrahydrocannabinol exposure induces a sensitization of dopamine D2/3 receptors in the mesoaccumbens and nigrostriatal systems. Neuropsychopharmacology 37, 2355–2367 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Tanda, G., Pontieri, F. E. & Di Chiara, G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common μ1 opioid receptor mechanism. Science 276, 2048–2050 (1997).THC increased extracellular dopamine concentrations in the nucleus accumbens shell.

    CAS  Google Scholar 

  65. 65

    Cadoni, C., Valentini, V. & Di Chiara, G. Behavioral sensitization to Δ9-tetrahydrocannabinol and cross-sensitization with morphine: differential changes in accumbal shell and core dopamine transmission. J. Neurochem. 106, 1586–1593 (2008)

    CAS  Google Scholar 

  66. 66

    Cadoni, C., Simola, N., Espa, E., Fenu, S. & Di Chiara, G. Strain dependence of adolescent cannabis influence on heroin reward and mesolimbic dopamine transmission in adult Lewis and Fischer 344 rats. Addict. Biol. 20, 132–142 (2015)

    CAS  Google Scholar 

  67. 67

    Bloomfield, M. A. P. et al. Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms. Biol. Psychiatry 75, 470–478 (2014).Dopamine synthesis capacity is reduced in long-term human cannabis users.

    CAS  Google Scholar 

  68. 68

    Volkow, N. D. et al. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc. Natl Acad. Sci. USA 111, E3149–E3156 (2014).Dopamine release is blunted in chronic human cannabis users.

    CAS  Google Scholar 

  69. 69

    van de Giessen, E. et al. Deficits in striatal dopamine release in cannabis dependence. Mol. Psychiatry (2016)

  70. 70

    Urban, N. B. L. et al. Dopamine release in chronic cannabis users: a [c-11]raclopride positron emission tomography study. Biol. Psychiatry 71, 677–683 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Mizrahi, R. et al. Dopamine response to psychosocial stress in chronic cannabis users: a PET study with [11C]-(+)-PHNO. Neuropsychopharmacology 38, 673–682 (2013)

    CAS  Google Scholar 

  72. 72

    Wiers, C. E. et al. Cannabis abusers show hypofrontality and blunted brain responses to a stimulant challenge in females but not in males. Neuropsychopharmacology 41, 2596–2605 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Leroy, C. et al. Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high-resolution PET study. Addict. Biol. 17, 981–990 (2012)

    CAS  Google Scholar 

  74. 74

    Zamberletti, E. et al. Gender-dependent behavioral and biochemical effects of adolescent Δ9-tetrahydrocannabinol in adult maternally deprived rats. Neuroscience 204, 245–257 (2012)

    CAS  Google Scholar 

  75. 75

    Cortright, J. J., Lorrain, D. S., Beeler, J. A., Tang, W. J. & Vezina, P. Previous exposure to Δ9-tetrahydrocannibinol enhances locomotor responding to but not self-administration of amphetamine. J. Pharmacol. Exp. Ther. 337, 724–733 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Gifford, A., Gardner, E. & Ashby Jr., C. R. The effect of intravenous administration of Δ9-tetrahydrocannabinol on the activity of A10 dopamine neurons recorded in vivo in anesthetized rats. Neuropsychobiology 36, 96–99 (1997)

    CAS  Google Scholar 

  77. 77

    French, E. D., Dillon, K. & Wu, X. Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport 8, 649–652 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Wu, X. & French, E. Effects of chronic Δ9-tetrahydrocannabinol on rat midbrain dopamine neurons: An electrophysiological assessment. Neuropharmacology 39, 391–398 (2000)

    CAS  Google Scholar 

  79. 79

    Diana, M., Melis, M., Muntoni, A. L. & Gessa, G. L. Mesolimbic dopaminergic decline after cannabinoid withdrawal. Proc. Natl Acad. Sci. USA 95, 10269–10273 (1998).Chronic THC exposure is associated with reduced dopamine neuron activity in the meso-accumbens.

    ADS  CAS  Google Scholar 

  80. 80

    Albrecht, D. S. et al. Striatal D2/D3 receptor availability is inversely correlated with cannabis consumption in chronic marijuana users. Drug Alcohol Depend. 128, 52–57 (2013)

    CAS  Google Scholar 

  81. 81

    Sevy, S. et al. Cerebral glucose metabolism and D2/D3 receptor availability in young adults with cannabis dependence measured with positron emission tomography. Psychopharmacology (Berl.) 197, 549–556 (2008)

    CAS  Google Scholar 

  82. 82

    Stokes, P. R. A. et al. History of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability. J Psychopharmacol. 26, 144–149 (2012)

    CAS  Google Scholar 

  83. 83

    Spiga, S., Lintas, A., Migliore, M. & Diana, M. Altered architecture and functional consequences of the mesolimbic dopamine system in cannabis dependence. Addict. Biol. 15, 266–276 (2010)

    CAS  Google Scholar 

  84. 84

    Behan, A. et al. Chronic adolescent exposure to Δ9-tetrahydrocannabinol in COMT mutant mice: Impact on indices of dopaminergic, endocannabinoid and GABAergic pathways. Neuropsychopharmacology 37, 1773–1783 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Kolb, B., Gorny, G., Limebeer, C. L. & Parker, L. A. Chronic treatment with Δ9-tetrahydrocannabinol alters the structure of neurons in the nucleus accumbens shell and medial prefrontal cortex of rats. Synapse 60, 429–436 (2006)

    CAS  Google Scholar 

  86. 86

    Renard, J., Krebs, M. O., Le Pen, G. & Jay, T. M. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology. Front. Neurosci. 8, 361 (2014)

    PubMed  PubMed Central  Google Scholar 

  87. 87

    Berghuis, P. et al. Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 316, 1212–1216 (2007)

    ADS  CAS  Google Scholar 

  88. 88

    Bonnin, A., de Miguel, R., Hernandez, M. L., Ramos, J. A. & Fernandez-Ruiz, J. J. The prenatal exposure to Δ9-tetrahydrocannabinol affects the gene expression and the activity of tyrosine hydroxylase during early brain development. Life Sci. 56, 2177–2184 (1995)

    CAS  Google Scholar 

  89. 89

    Walters, D. E. & Carr, L. A. Perinatal exposure to cannabinoids alters neurochemical development in rat brain. Pharmacol. Biochem. Behav. 29, 213–216 (1988)

    CAS  Google Scholar 

  90. 90

    DiNieri, J. A. et al. Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring. Biol. Psychiatry 70, 763–769 (2011).Prenatal cannabis exposure decreases dopamine receptor D 2 messenger RNA expression in the ventral striatum of offspring in humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Garcia-Gil, L. et al. Perinatal Δ9-tetrahydrocannabinol exposure alters the responsiveness of hypothalamic dopaminergic neurons to dopamine-acting drugs in adult rats. Neurotoxicol. Teratol. 19, 477–487 (1997)

    CAS  Google Scholar 

  92. 92

    Mokler, D. J., Robinson, S. E., Johnson, J. H., Hong, J. S. & Rosecrans, J. A. Neonatal administration of Δ9-tetrahydrocannabinol (THC) alters the neurochemical response to stress in the adult Fischer-344 rat. Neurotoxicol. Teratol. 9, 321–327 (1987)

    CAS  Google Scholar 

  93. 93

    Scherma, M. et al. Adolescent Δ9-tetrahydrocannabinol exposure alters WIN55,212–2 self-administration in adult rats. Neuropsychopharmacology 41, 1416–1426 (2016)

    CAS  Google Scholar 

  94. 94

    Bossong, M. G. et al. Δ9-tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacology 34, 759–766 (2009).Combined analysis of two previous PET studies showing that acute THC administration causes dopamine release in humans.

    CAS  Google Scholar 

  95. 95

    Stokes, P., Mehta, M., Curran, H., Breen, G. & Grasby, P. Can recreational doses of THC produce significant dopamine release in the human striatum? Neuroimage 48, 186–190 (2009)

    Google Scholar 

  96. 96

    Mawlawi, O. et al. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D2 receptor parameter measurements in ventral striatum. J. Cereb. Blood Flow Metab. 21, 1034–1057 (2001)

    CAS  Google Scholar 

  97. 97

    Do we need an ethics of self-organizing tissue? Nat. Methods 12, 895 (2015)

  98. 98

    Lindgren, J. E., Ohlsson, A., Agurell, S., Hollister, L. & Gillespie, H. Clinical effects and plasma levels of Δ9-tetrahydrocannabinol (Δ9-THC) in heavy and light users of cannabis. Psychopharmacology (Berl.) 74, 208–212 (1981)

    CAS  Google Scholar 

  99. 99

    Hardwick, S. K. L. Home Office Cannabis Potency Study (Home Office, 2008)

  100. 100

    Hunault, C. C. et al. Disposition of smoked cannabis with high Δ9-tetrahydrocannabinol content: a kinetic model. Toxicol. Appl. Pharmacol. 246, 148–153 (2010)

    CAS  Google Scholar 

  101. 101

    Banerjee, S. P., Snyder, S. H. & Mechoulam, R. Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes. J. Pharmacol. Exp. Ther. 194, 74–81 (1975)

    CAS  Google Scholar 

  102. 102

    Bloomfield, M. A., Morgan, C. J., Kapur, S., Curran, H. V. & Howes, O. D. The link between dopamine function and apathy in cannabis users: an [18F]-DOPA PET imaging study. Psychopharmacology (Berl.) 231, 2251–2259 (2014)

    CAS  Google Scholar 

  103. 103

    von Sydow, K., Lieb, R., Pfister, H., Hofler, M. & Wittchen, H. U. What predicts incident use of cannabis and progression to abuse and dependence? A 4-year prospective examination of risk factors in a community sample of adolescents and young adults. Drug Alcohol Depend. 68, 49–64 (2002)

    Google Scholar 

  104. 104

    Carlini, E. A., Lindsey, C. J. & Tufik, S. Cannabis, catecholamines, rapid eye movement sleep and aggressive behaviour. Br. J. Pharmacol. 61, 371–379 (1977)

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    MacLean, K. I. & Littleton, J. M. Environmental stress as a factor in the response of rat brain catecholamine metabolism to Δ8-tetrahydrocannabinol. Eur. J. Pharmacol. 41, 171–182 (1977)

    CAS  Google Scholar 

  106. 106

    Lomax, P. Acute tolerance to the hypothermic effect of marihuana in the rat. Res. Commun. Chem. Pathol. Pharmacol. 2, 159–167 (1971)

    CAS  Google Scholar 

  107. 107

    Andén, N. E. Dopamine turnover in the corpus striatum and the lumbic system after treatment with neuroleptic and anti-acetylcholine drugs. J. Pharm. Pharmacol. 24, 905–906 (1972)

    Google Scholar 

  108. 108

    Hattendorf, C., Hattendorf, M., Coper, H. & Fernandes, M. Interaction between Δ9-tetrahydrocannabinol and d-amphetamine. Psychopharmacology (Berl.) 54, 177–182 (1977)

    CAS  Google Scholar 

  109. 109

    Williams, C. M., Rogers, P. J. & Kirkham, T. C. Hyperphagia in pre-fed rats following oral Δ9-THC. Physiol. Behav. 65, 343–346 (1998)

    CAS  Google Scholar 

  110. 110

    Foltin, R. W., Brady, J. V. & Fischman, M. W. Behavioral analysis of marijuana effects on food intake in humans. Pharmacol. Biochem. Behav. 25, 577–582 (1986)

    CAS  PubMed  Google Scholar 

  111. 111

    Ungerstedt, U. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scand. Suppl. 367, 95–122 (1971)

    CAS  Google Scholar 

  112. 112

    Verty, A., McGregor, I. & Mallet, P. The dopamine receptor antagonist SCH 23390 attenuates feeding induced by Δ9-tetrahydrocannabinol. Brain Res. 1020, 188–195 (2004)

    CAS  Google Scholar 

  113. 113

    Koch, M. et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519, 45–50 (2015)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Andrews, Z. B. et al. Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. J. Neurosci. 29, 14057–14065 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Fergusson, D. M., Horwood, L. J. & Beautrais, A. L. Cannabis and educational achievement. Addiction 98, 1681–1692 (2003).Longitudinal birth cohort study indicating that cannabis use in adolescents and early adults is associated with reduced educational achievement.

    Google Scholar 

  116. 116

    Hooker, W. D. & Jones, R. T. Increased susceptibility to memory intrusions and the Stroop interference effect during acute marijuana intoxication. Psychopharmacology (Berl.) 91, 20–24 (1987)

    CAS  Google Scholar 

  117. 117

    Ranganathan, M. & D’Souza, D. C. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology (Berl.) 188, 425–444 (2006)

    CAS  Google Scholar 

  118. 118

    McGlothlin, W. H. W. L. The marihuana problem: an overview. Am. J. Psychiatry 125, 126–134 (1968)

    CAS  Google Scholar 

  119. 119

    Levy, R. & Dubois, B. Apathy and the functional anatomy of the prefrontal cortex–basal ganglia circuits. Cereb. Cortex 16, 916–928 (2005)

    Google Scholar 

  120. 120

    Goldman-Rakic, P. S. Regional and cellular fractionation of working memory. Proc. Natl Acad. Sci. USA 93, 13473–13480 (1996)

    ADS  CAS  Google Scholar 

  121. 121

    Sawaguchi, T. & Goldman-Rakic, P. S. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251, 947–950 (1991)

    ADS  CAS  PubMed  Google Scholar 

  122. 122

    Nava, F., Carta, G. & Gessa, G. Permissive role of dopamine D2 receptors in the hypothermia induced by Δ9-tetrahydrocannabinol in rats. Pharmacol. Biochem. Behav. 66, 183–187 (2000)

    CAS  Google Scholar 

  123. 123

    D’Souza, D. C. et al. Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Δ9-tetrahydrocannabinol in humans. Psychopharmacology (Berl.) 198, 587–603 (2008)

    Google Scholar 

  124. 124

    Tunbridge, E. M. et al. Genetic moderation of the effects of cannabis: catechol-O-methyltransferase (COMT) affects the impact of Δ9-tetrahydrocannabinol (THC) on working memory performance but not on the occurrence of psychotic experiences. J. Psychopharmacol. 29, 1146–1151 (2015)

    CAS  Google Scholar 

  125. 125

    Paule, M. G. et al. Chronic marijuana smoke exposure in the rhesus monkey. II: Effects on progressive ratio and conditioned position responding. J. Pharmacol. Exp. Ther. 260, 210–222 (1992)

    CAS  Google Scholar 

  126. 126

    Campbell, I. The amotivational syndrome and cannabis use with emphasis on the Canadian scene. Ann. NY Acad. Sci. 282, 33–36 (1976)

    ADS  CAS  Google Scholar 

  127. 127

    Howes, O. D. et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch. Gen. Psychiatry 69, 776–786 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Voruganti, L. N., Slomka, P., Zabel, P., Mattar, A. & Awad, A. G. Cannabis induced dopamine release: an in-vivo SPECT study. Psychiatry Res. 107, 173–177 (2001)

    CAS  Google Scholar 

  129. 129

    Mizrahi, R. et al. Stress-induced dopamine response in subjects at clinical high risk for schizophrenia with and without concurrent cannabis use. Neuropsychopharmacology 39, 1479–1489 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Thompson, J. L. et al. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol. Psychiatry 18, 909–915 (2013)

    CAS  Google Scholar 

  131. 131

    Leweke, F. M. et al. Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: Impact of cannabis use. Schizophr. Res. 94, 29–36 (2007)

    Google Scholar 

  132. 132

    Leweke, F. M. et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry 2, e94 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Kearn, C. S., Blake-Palmer, K., Daniel, E., Mackie, K. & Glass, M. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: a mechanism for receptor cross-talk? Mol. Pharmacol. 67, 1697–1704 (2005)

    CAS  Google Scholar 

  134. 134

    Di Forti, M. et al. Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. Biol. Psychiatry 72, 811–816 (2012)

    CAS  Google Scholar 

  135. 135

    Parsons, L. H. & Hurd, Y. L. Endocannabinoid signalling in reward and addiction. Nat. Rev. Neuroci. 16, 579–594 (2015).Impaired endocannabinoid signalling dysregulates synaptic plasticity and increases stress responsivity, negative emotional states and cravings that propel addiction.

    CAS  Google Scholar 

  136. 136

    Lecca, S., Melis, M., Luchicchi, A., Muntoni, A. L. & Pistis, M. Inhibitory inputs from rostromedial tegmental neurons regulate spontaneous activity of midbrain dopamine cells and their responses to drugs of abuse. Neuropsychopharmacology 37, 1164–1176 (2012)

    CAS  Google Scholar 

  137. 137

    Marinelli, S. et al. N-arachidonoyl-dopamine tunes synaptic transmission onto dopaminergic neurons by activating both cannabinoid and vanilloid receptors. Neuropsychopharmacology 32, 298–308 (2007)

    CAS  Google Scholar 

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We thank V. M. Rajagopal and Nature for assistance with illustrations. This work was funded by a Medical Research Council (UK) Grant to O.D.H. (MC-A656-5QD30).

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M.A.P.B. and O.D.H. conceptualized this review. M.A.P.B. and A.H.A. systematically reviewed the literature. All the authors contributed intellectually.

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Correspondence to Oliver D. Howes.

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M.A.P.B. conducts research funded by the Medical Research Council (UK), the National Institute of Health Research (UK) and the British Medical Association. A.H.A. conducts research funded by the Medical Research Council (UK) and Kings College London. N.D.V. is Director of the National Institute on Drug Abuse (USA). O.D.H. conducts research funded by the Medical Research Council (UK), the National Institute of Health Research (UK) and the Maudsley Charity. O.D.H. has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Astra-Zeneca, BMS, Eli Lilly, Jansenn, Lundbeck, Lyden-Delta, Servier, and Roche. Neither O.D.H. nor his family have been employed by or have holdings/a financial stake in any biomedical company.

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Nature thanks P. Fadda and R. Mechoulam for their contribution to the peer review of this work.

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Bloomfield, M., Ashok, A., Volkow, N. et al. The effects of Δ9-tetrahydrocannabinol on the dopamine system. Nature 539, 369–377 (2016).

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