Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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)
EMCDDA. European Drug Report 2015: Trends and Developments (European Monitoring Centre for Drugs and Drug Addiction, Lisbon, 2015)
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)
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)
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)
Horwood, L. J. et al. Cannabis and depression: an integrative data analysis of four Australasian cohorts. Drug Alcohol Depend. 126, 369–378 (2012)
Silins, E. et al. Young adult sequelae of adolescent cannabis use: an integrative analysis. Lancet Psychiatry 1, 286–293 (2014)
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)
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)
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)
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)
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)
Spaderna, M., Addy, P. H. & D’Souza, D. C. Spicing things up: synthetic cannabinoids. Psychopharmacology (Berl.) 228, 525–540 (2013)
Benjamin, D. M. & Fossler, M. J. Edible cannabis products: it is time for FDA oversight. J. Clin. Pharmacol. (2016)
Varlet, V. et al. Drug vaping applied to cannabis: Is “Cannavaping” a therapeutic alternative to marijuana? Sci. Rep. 6, 25599 (2016)
Vallee, M. et al. Pregnenolone can protect the brain from cannabis intoxication. Science 343, 94–98 (2014)
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.
Elphick, M. R. & Egertova, M. The neurobiology and evolution of cannabinoid signalling. Phil. Trans. R. Soc. Lond. B 356, 381–408 (2001)
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)
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)
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)
Hollister, L. E. & Gillespie, H. K. Action of Δ9-tetrahydrocannabinol. An approach to the active metabolite hypothesis. Clin. Pharmacol. Ther. 18, 714–719 (1975)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
Nahas, G. G. in Medical Aspects of Drug Abuse (ed. R. W. Richter ) 16–36 (Harper & Row, 1975)
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)
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)
French, E. Δ9-Tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB1 but not opioid receptors. Neurosci. Lett. 226, 159–162 (1997)
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)
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)
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)
Volkow, N. D. et al. Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication. Psychiatry Res. 67, 29–38 (1996)
Pertwee, R. G. & Ross, R. A. Cannabinoid receptors and their ligands. Prostaglandins Leukot. Essent. Fatty Acids 66, 101–121 (2002)
Borgwardt, S. J. et al. Neural basis of Δ9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol. Psychiatry 64, 966–973 (2008)
Bhattacharyya, S. et al. Opposite effects of Δ9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35, 764–774 (2010)
van Hell, H. H. et al. Involvement of the endocannabinoid system in reward processing in the human brain. Psychopharmacology (Berl.) 219, 981–990 (2012)
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)
Stokes, P. R. et al. Significant decreases in frontal and temporal [11C]-raclopride binding after THC challenge. Neuroimage 52, 1521–1527 (2010)
Barkus, E. et al. Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study. J. Psychopharmacol. 25, 1462–1468 (2011)
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)
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)
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)
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)
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)
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)
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.
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)
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)
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.
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.
van de Giessen, E. et al. Deficits in striatal dopamine release in cannabis dependence. Mol. Psychiatry http://dx.doi.org/10.1038/mp.2016.21 (2016)
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)
Mizrahi, R. et al. Dopamine response to psychosocial stress in chronic cannabis users: a PET study with [11C]-(+)-PHNO. Neuropsychopharmacology 38, 673–682 (2013)
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)
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)
Zamberletti, E. et al. Gender-dependent behavioral and biochemical effects of adolescent Δ9-tetrahydrocannabinol in adult maternally deprived rats. Neuroscience 204, 245–257 (2012)
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)
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)
French, E. D., Dillon, K. & Wu, X. Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport 8, 649–652 (1997)
Wu, X. & French, E. Effects of chronic Δ9-tetrahydrocannabinol on rat midbrain dopamine neurons: An electrophysiological assessment. Neuropharmacology 39, 391–398 (2000)
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.
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)
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)
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)
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)
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)
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)
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)
Berghuis, P. et al. Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 316, 1212–1216 (2007)
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)
Walters, D. E. & Carr, L. A. Perinatal exposure to cannabinoids alters neurochemical development in rat brain. Pharmacol. Biochem. Behav. 29, 213–216 (1988)
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.
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)
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)
Scherma, M. et al. Adolescent Δ9-tetrahydrocannabinol exposure alters WIN55,212–2 self-administration in adult rats. Neuropsychopharmacology 41, 1416–1426 (2016)
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.
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)
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)
Do we need an ethics of self-organizing tissue? Nat. Methods 12, 895 (2015)
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)
Hardwick, S. K. L. Home Office Cannabis Potency Study (Home Office, 2008)
Hunault, C. C. et al. Disposition of smoked cannabis with high Δ9-tetrahydrocannabinol content: a kinetic model. Toxicol. Appl. Pharmacol. 246, 148–153 (2010)
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)
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)
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)
Carlini, E. A., Lindsey, C. J. & Tufik, S. Cannabis, catecholamines, rapid eye movement sleep and aggressive behaviour. Br. J. Pharmacol. 61, 371–379 (1977)
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)
Lomax, P. Acute tolerance to the hypothermic effect of marihuana in the rat. Res. Commun. Chem. Pathol. Pharmacol. 2, 159–167 (1971)
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)
Hattendorf, C., Hattendorf, M., Coper, H. & Fernandes, M. Interaction between Δ9-tetrahydrocannabinol and d-amphetamine. Psychopharmacology (Berl.) 54, 177–182 (1977)
Williams, C. M., Rogers, P. J. & Kirkham, T. C. Hyperphagia in pre-fed rats following oral Δ9-THC. Physiol. Behav. 65, 343–346 (1998)
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)
Ungerstedt, U. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scand. Suppl. 367, 95–122 (1971)
Verty, A., McGregor, I. & Mallet, P. The dopamine receptor antagonist SCH 23390 attenuates feeding induced by Δ9-tetrahydrocannabinol. Brain Res. 1020, 188–195 (2004)
Koch, M. et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519, 45–50 (2015)
Andrews, Z. B. et al. Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. J. Neurosci. 29, 14057–14065 (2009)
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.
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)
Ranganathan, M. & D’Souza, D. C. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology (Berl.) 188, 425–444 (2006)
McGlothlin, W. H. W. L. The marihuana problem: an overview. Am. J. Psychiatry 125, 126–134 (1968)
Levy, R. & Dubois, B. Apathy and the functional anatomy of the prefrontal cortex–basal ganglia circuits. Cereb. Cortex 16, 916–928 (2005)
Goldman-Rakic, P. S. Regional and cellular fractionation of working memory. Proc. Natl Acad. Sci. USA 93, 13473–13480 (1996)
Sawaguchi, T. & Goldman-Rakic, P. S. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251, 947–950 (1991)
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)
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)
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)
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)
Campbell, I. The amotivational syndrome and cannabis use with emphasis on the Canadian scene. Ann. NY Acad. Sci. 282, 33–36 (1976)
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)
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)
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)
Thompson, J. L. et al. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol. Psychiatry 18, 909–915 (2013)
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)
Leweke, F. M. et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry 2, e94 (2012)
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)
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)
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.
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)
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)
Acknowledgements
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).
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
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.
Additional information
Reviewer Information
Nature thanks P. Fadda and R. Mechoulam for their contribution to the peer review of this work.
Rights and permissions
About this article
Cite this article
Bloomfield, M., Ashok, A., Volkow, N. et al. The effects of Δ9-tetrahydrocannabinol on the dopamine system. Nature 539, 369–377 (2016). https://doi.org/10.1038/nature20153
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature20153
This article is cited by
-
Genome-wide DNA methylation association study of recent and cumulative marijuana use in middle aged adults
Molecular Psychiatry (2023)
-
Rewiring the future: drugs abused in adolescence may predispose to mental illness in adult life by altering dopamine axon growth
Journal of Neural Transmission (2023)
-
Repeated chemogenetic activation of dopaminergic neurons induces reversible changes in baseline and amphetamine-induced behaviors
Psychopharmacology (2023)
-
Integrated Transcriptomics and Network Analysis Identified Altered Neural Mechanisms in Frontal Aging Brain-Associated Alzheimer’s Disease
Biochemical Genetics (2023)
-
Identification of ∆9-tetrahydrocannabinol (THC) impairment using functional brain imaging
Neuropsychopharmacology (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.