Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers
Open accessAbstract
Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB1 (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ∼4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB1 receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB1 receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Human brain imaging studies report reduced cannabinoid CB1 receptors in cannabis abusers and alcoholics.
“Indeed, human brain imaging studies have reported reductions of cannabinoid CB1 receptors in cannabis abusers and alcoholics.”
From Neurobiology of addiction: a neurocircuitry analysis (2016) · cites this paper as [86]
The Discussion (page unavailable) reports reduced cortical CB1 receptor binding in chronic daily cannabis smokers, measured by PET. The paper does not report a comparable finding in alcoholics; its Subjects section says participants did not currently abuse drugs other than cannabis. (LLM, conf=0.90)
Experimental — accuracy not yet measuredDirect activation of CB1 receptors with plant-derived cannabinoids over an extended period leads to down-regulation of CB1 receptors.
“as direct activation of CB1 receptors with plant-derived cannabinoids over an extended period of time leads to down-regulation of CB1 receptors52, 53”
From Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study (2013) · cites this paper as [52]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., Mazoyer, B., & Joliot, M. (2002) · NeuroImage · doi:10.1006/nimg.2001.0978 · Cited by 16,319 · see citing works
Statistical parametric maps in functional imaging: A general linear approach
Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J. ‐., Frith, C. D., & Frackowiak, R. S. J. (1994) · Human Brain Mapping · doi:10.1002/hbm.460020402 · Cited by 9,688 · see citing works
International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors
Howlett, A. C., Barth, F., Bonner, T. I., Cabral, G., Casellas, P., Devane, W. A., Felder, C. C., Herkenham, M., Mackie, K., Martin, B. R., et al. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.2.161 · Cited by 2,819 · see citing works
Cannabinoid receptor localization in brain.
Herkenham, M., Lynn, A. B., Little, M. D., Johnson, M. R., Melvin, L. S., de Costa, B. R., & Rice, K. C. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.5.1932 · Cited by 2,321 · see citing works
Consensus Nomenclature for <i>in vivo</i> Imaging of Reversibly Binding Radioligands
Innis, R. B., Cunningham, V. J., Delforge, J., Fujita, M., Gjedde, A., Gunn, R. N., Holden, J., Houle, S., Huang, S.-C., Ichise, M., et al. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600493 · Cited by 1,955 · see citing works
Self-citationEndocannabinoid Signaling in the Brain
Wilson, R. I., & Nicoll, R. A. (2002) · Science · doi:10.1126/science.1063545 · Cited by 1,260 · see citing works
Adverse health effects of non-medical cannabis use
Hall, W., & Degenhardt, L. (2009) · The Lancet · doi:10.1016/s0140-6736(09)61037-0 · Cited by 1,134 · see citing works
Glass, M., Faull, R. L. M., & Dragunow, M. (1997) · Neuroscience · doi:10.1016/s0306-4522(96)00428-9 · Cited by 1,052 · see citing works
Degenhardt, L., Chiu, W.-T., Sampson, N., Kessler, R. C., Anthony, J. C., Angermeyer, M., Bruffaerts, R., de Girolamo, G., Gureje, O., Huang, Y., et al. (2008) · PLoS Medicine · doi:10.1371/journal.pmed.0050141 · Cited by 796 · see citing works
Mawlawi, O., Martinez, D., Slifstein, M., Broft, A., Chatterjee, R., Hwang, D.-R., Huang, Y., Simpson, N., Ngo, K., Van Heertum, R., et al. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200109000-00002 · Cited by 525 · see citing works
Huestis, M. A., Gorelick, D. A., Heishman, S. J., Preston, K. L., Nelson, R. A., Moolchan, E. T., & Frank, R. A. (2001) · Archives of General Psychiatry · doi:10.1001/archpsyc.58.4.322 · Cited by 479 · see citing works
Self-citationNeurocognitive performance during acute THC intoxication in heavy and occasional cannabis users
Ramaekers, J. G., Kauert, G. F., Theunissen, E. L., Toennes, S. W., & Moeller, M. R. (2008) · Journal of Psychopharmacology · doi:10.1177/0269881108092393 · Cited by 374 · see citing works
Abstinence symptoms following smoked marijuana in humans
Haney, M., Ward, A. S., Comer, S. D., Foltin, R. W., & Fischman, M. W. (1999) · Psychopharmacology · doi:10.1007/s002130050849 · Cited by 354 · see citing works
Bimodal control of stimulated food intake by the endocannabinoid system
Bellocchio, L., Lafenêtre, P., Cannich, A., Cota, D., Puente, N., Grandes, P., Chaouloff, F., Piazza, P. V., & Marsicano, G. (2010) · Nature Neuroscience · doi:10.1038/nn.2494 · Cited by 282 · see citing works
Breivogel, C. S., Childers, S. R., Deadwyler, S. A., Hampson, R. E., Vogt, L. J., & Sim‐Selley, L. J. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0732447.x · Cited by 273 · see citing works
Regulation of Cannabinoid CB1 Receptors in the Central Nervous System by Chronic Cannabinoids
Sim‐Selley, L. J. (2003) · Critical Reviews in Neurobiology · doi:10.1615/critrevneurobiol.v15.i2.10 · Cited by 271 · see citing works
D’Souza, D. C., Ranganathan, M., Braley, G., Gueorguieva, R. V., Zimolo, Z., Cooper, T. B., Perry, E. B., & Krystal, J. H. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301643 · Cited by 263 · see citing works
Cannabinoid tolerance and dependence: A review of studies in laboratory animals
González, S. R., Cebeira, M., & Fernández‐Ruíz, J. (2005) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2005.01.028 · Cited by 258 · see citing works
Marijuana Craving Questionnaire: development and initial validation of a self‐report instrument
Heishman, S. J., Singleton, E. G., & Liguori, A. (2001) · Addiction · doi:10.1046/j.1360-0443.2001.967102312.x · Cited by 232 · see citing works
Clinical Relevance of Cannabis Tolerance and Dependence
Jones, R. T., Benowitz, N. L., & Herning, R. I. (1981) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1981.tb02589.x · Cited by 191 · see citing works
Gandelman, M. S., Baldwin, R. M., Zoghbi, S. S., Zea‐Ponce, Y., & Innis, R. B. (1994) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600830718 · Cited by 191 · see citing works
Self-citationOviedo, A., Glowa, J. R., & Herkenham, M. A. (1993) · Brain Research · doi:10.1016/0006-8993(93)90220-h · Cited by 179 · see citing works
Zoghbi, S. S., Shetty, H. U., Ichise, M., et al. (2006) · PubMed · Cited by 170 · see citing works
Self-citationHuestis, M. A., Boyd, S. J., Heishman, S. J., Preston, K. L., BONNET, D., Fur, G. L., & Gorelick, D. A. (2007) · Psychopharmacology · doi:10.1007/s00213-007-0861-5 · Cited by 166 · see citing works
Self-citationCannabis reinforcement and dependence: role of the cannabinoid CB1 receptor.
Cooper, Z. D., & Haney, M. (2008) · Addiction Biology · doi:10.1111/j.1369-1600.2007.00095.x · Cited by 158 · see citing works
Innis, R. B., Malison, R. T., Al‐Tikriti, M. S., Hoffer, P. B., Sybirska, E. H., Seibyl, J. P., Zoghbi, S. S., Baldwin, R. M., Laruelle, M. A., Smith, E. O., et al. (1992) · Synapse · doi:10.1002/syn.890100302 · Cited by 155 · see citing works
Self-citationVillares, J. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2006.11.012 · Cited by 134 · see citing works
Rinaldi, M. L., Pialot, F., Congy, C., Redon, E., Barth, F., Bachy, A., Brelière, J.-C., Soubrié, P., & Fur, G. L. (1996) · Life Sciences · doi:10.1016/0024-3205(96)00085-9 · Cited by 132 · see citing works
Actions of delta-9-tetrahydrocannabinol in cannabis: Relation to use, abuse, dependence
Cooper, Z. D., & Haney, M. (2009) · International Review of Psychiatry · doi:10.1080/09540260902782752 · Cited by 127 · see citing works
Sim‐Selley, L. J., & Martin, B. R. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.035618 · Cited by 125 · see citing works
Cota, D. (2007) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.764 · Cited by 124 · see citing works
Signaling pathways involved in the development of cannabinoid tolerance
Martin, B. R., Sim‐Selley, L. J., & Selley, D. E. (2004) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2004.04.005 · Cited by 115 · see citing works
Sim‐Selley, L. J., Schechter, N. S., Rorrer, W. K., Dalton, G. D., Hernandez, J., Martin, B. R., & Selley, D. E. (2006) · Molecular Pharmacology · doi:10.1124/mol.105.019612 · Cited by 115 · see citing works
Lowe, R. H., Abraham, T. T., Darwin, W. D., Herning, R. I., Cadet, J. L., & Huestis, M. A. (2009) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2009.05.027 · Cited by 113 · see citing works
Self-citationDo Δ9‐tetrahydrocannabinol concentrations indicate recent use in chronic cannabis users?
Karschner, E. L., Schwilke, E. W., Lowe, R. H., Darwin, W. D., Pope, H. G., Herning, R. I., Cadet, J. L., & Huestis, M. A. (2009) · Addiction · doi:10.1111/j.1360-0443.2009.02705.x · Cited by 106 · see citing works
Self-citationKarschner, E. L., Schwilke, E. W., Lowe, R. H., Darwin, W. D., Herning, R. I., Cadet, J. L., & Huestis, M. A. (2009) · Journal of Analytical Toxicology · doi:10.1093/jat/33.8.469 · Cited by 106 · see citing works
Self-citationTerry, G. E., Hirvonen, J., Liow, J., Zoghbi, S. S., Gladding, R. L., Tauscher, J. T., Schaus, J. M., Phebus, L. A., Felder, C. C., Morse, C. L., et al. (2009) · Journal of Nuclear Medicine · doi:10.2967/jnumed.109.067074 · Cited by 101 · see citing works
Self-citationD’Souza, D. C. (2007) · International review of neurobiology · doi:10.1016/s0074-7742(06)78010-2 · Cited by 96 · see citing works
McKinney, D. L., Cassidy, M. P., Collier, L., Martin, B. R., Wiley, J. L., Selley, D. E., & Sim‐Selley, L. J. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.130328 · Cited by 89 · see citing works
Donohue, S. R., Krushinski, J. H., Pike, V. W., Chernet, E., Phebus, L. A., Chesterfield, A. K., Felder, C. C., Halldin, C., & Schaus, J. M. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800416m · Cited by 83 · see citing works
Self-citationThe effects of Δ9-tetrahydrocannabinol physical dependence on brain cannabinoid receptors
Breivogel, C. S., Scates, S. M., Beletskaya, I. O., et al. (2003) · European Journal of Pharmacology · doi:10.1016/s0014-2999(02)02854-6 · Cited by 54 · see citing works
Terry, G., Liow, J.-S., Chernet, E., Zoghbi, S. S., Phebus, L., Felder, C. C., Tauscher, J., Schaus, J. M., Pike, V. W., Halldin, C., et al. (2008) · NeuroImage · doi:10.1016/j.neuroimage.2008.03.004 · Cited by 51 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Neurobiology of addiction: a neurocircuitry analysis
Koob, G. F., & Volkow, N. D. (2016) · The Lancet Psychiatry · doi:10.1016/s2215-0366(16)00104-8 · Cited by 3,698 · see citing works
Self-citationAdverse health effects of marijuana use.
Volkow, N. D., Baler, R. D., Compton, W. M., & Weiss, S. R. B. (2014) · New England Journal of Medicine · doi:10.1056/nejmra1402309 · Cited by 2,774 · see citing works
Self-citationHippocampal GABAergic Inhibitory Interneurons
Pelkey, K. A., Chittajallu, R., Craig, M. T., Tricoire, L., Wester, J. C., & McBain, C. J. (2017) · Physiological Reviews · doi:10.1152/physrev.00007.2017 · Cited by 889 · see citing works
Effects of Cannabis Use on Human Behavior, Including Cognition, Motivation, and Psychosis: A Review
Volkow, N. D., Swanson, J. M., Evins, A. E., DeLisi, L. E., Meier, M. H., Gonzalez, R., Bloomfield, M. A. P., Curran, H. V., & Baler, R. (2016) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2015.3278 · Cited by 867 · see citing works
Self-citationMultiple Functions of Endocannabinoid Signaling in the Brain
Katona, I., & Freund, T. F. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-062111-150420 · Cited by 630 · see citing works
Cannabis use and cannabis use disorder
Connor, J. P., Stjepanović, D., Le Foll, B., Hoch, E., Budney, A. J., & Hall, W. D. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00247-4 · Cited by 552 · see citing works
Neumeister, A., Normandin, M. D., Pietrzak, R. H., Piomelli, D., Zheng, M. Q., Gujarro-Anton, A., Potenza, M. N., Bailey, C. R., Lin, S. F., Najafzadeh, S., et al. (2013) · Molecular Psychiatry · doi:10.1038/mp.2013.61 · Cited by 361 · see citing works
Long-term effects of marijuana use on the brain
Filbey, F. M., Aslan, S., Calhoun, V. D., Spence, J. S., Damaraju, E., Caprihan, A., & Segall, J. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1415297111 · Cited by 249 · see citing works
The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects
van Amsterdam, J., Brunt, T., & van den Brink, W. (2015) · Journal of Psychopharmacology · doi:10.1177/0269881114565142 · Cited by 244 · see citing works
The endocannabinoid system as a target for novel anxiolytic drugs
Patel, S., Hill, M. N., Cheer, J. F., Wotjak, C. T., & Holmes, A. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.12.033 · Cited by 233 · see citing works
Cell-specific STORM super-resolution imaging reveals nanoscale organization of cannabinoid signaling
Dudok, B., Barna, L., Ledri, M., Szabó, S. I., Szabadits, E., Pintér, B., Woodhams, S. G., Henstridge, C. M., Balla, G. Y., Nyilas, R., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.3892 · Cited by 227 · see citing works
The cannabis withdrawal syndrome: current insights
Bonnet, U., & Preuss, U. (2017) · Substance Abuse and Rehabilitation · doi:10.2147/sar.s109576 · Cited by 221 · see citing works
Lisdahl, K. M., Wright, N. E., Medina-Kirchner, C., Maple, K. E., & Shollenbarger, S. (2014) · Current Addiction Reports · doi:10.1007/s40429-014-0019-6 · Cited by 160 · see citing works
Li, C., Chen, M., Lin, W., Hong, C., Yang, B., Liu, R., Tu, P., & Su, T. (2016) · Human Brain Mapping · doi:10.1002/hbm.23085 · Cited by 152 · see citing works
Self-citationCeccarini, J., Hompes, T., Verhaeghen, A., Casteels, C., Peuskens, H., Bormans, G., Claes, S., & Van Laere, K. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.0849-13.2014 · Cited by 111 · see citing works
Klugah‐Brown, B., Di, X., Zweerings, J., Mathiak, K., Becker, B., & Biswal, B. (2020) · Human Brain Mapping · doi:10.1002/hbm.25085 · Cited by 86 · see citing works
Neuroimaging studies of acute effects of THC and CBD in humans and animals: a systematic review
Batalla, A., Crippa, J. A., Busatto, G. F., Guimaraes, F. S., Zuardi, A. W., Valverde, O., Atakan, Z., McGuire, P. K., Bhattacharyya, S., & Martín-Santos, R. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113199990432 · Cited by 91 · see citing works
Boileau, I., Mansouri, E., Williams, B., Le Foll, B., Rusjan, P., Mizrahi, R., Tyndale, R. F., Huestis, M. A., Payer, D. E., Wilson, A. A., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.04.012 · Cited by 82 · see citing works
Self-citationFunctional Connectivity Disruption in Neonates with Prenatal Marijuana Exposure
Grewen, K., Salzwedel, A. P., & Gao, W. (2015) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2015.00601 · Cited by 72 · see citing works
Shollenbarger, S. G., Price, J., Wieser, J., & Lisdahl, K. (2015) · NeuroImage: Clinical · doi:10.1016/j.nicl.2015.03.024 · Cited by 64 · see citing works
Neumeister, A. (2013) · Depression and Anxiety · doi:10.1002/da.22031 · Cited by 47 · see citing works
De Aquino, J. P., Sofuoglu, M., Stefanovics, E. A., & Rosenheck, R. A. (2020) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990.2020.1818248 · Cited by 6 · see citing works
- Authors
- Hirvonen, J., Goodwin, R. S., Li, C.-T., Terry, G. E., Zoghbi, S. S., Morse, C., Pike, V. W., Volkow, N. D., Huestis, M. A., & Innis, R. B.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Innis, R B
- Venue
- Molecular Psychiatry
- Published
- 2011-07-12
- Volume
- 17
- Issue
- 6
- Pages
- 642-649
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3223558
- OpenAlex
- W2154855551
- Semantic Scholar
- 36c693686b4d8fe3ae23eee44b913f0668208db3
- Cited by
- 587
- References
- 42
- Citations by year
- 2026: 41 · 2025: 32 · 2024: 25 · 2023: 35 · 2022: 48 · 2021: 59 · 2020: 58 · 2019: 42 · 2018: 38 · 2017: 41 · 2016: 50 · 2015: 39 · 2014: 33 · 2013: 29 · 2012: 16
- FWCI
- 18.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (Z01MH002852, ZIAMH002852)
- National Institute on Drug Abuse (Z01DA000413)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CB1 receptor, receptor down-regulation, cannabis use disorder, neural adaptation, cannabis abstinence, receptor density
- MeSH terms
- Adult, Cerebral Cortex, Fluorine Radioisotopes, Humans, Male, Marijuana Smoking, Pyrrolidinones, Substance Withdrawal Syndrome, Time Factors, Down-Regulation, Receptor, Cannabinoid, CB1, Positron-Emission Tomography, Functional Neuroimaging
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
