{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:05:01Z","timestamp":1780459501969,"version":"3.54.1"},"reference-count":60,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"District Agency for Higher Education, Science, and Technology of Bogota-Colombia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Cocaine use disorder (CUD) remains a major global health concern, with no FDA-approved pharmacological treatments currently available. Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa L., has shown promising preclinical effects in disrupting the consolidation and retrieval of drug-associated memories, thereby attenuating relapse-like behaviors. Objectives: The present study evaluated the effects of a low-THC CBD-rich cannabis extract (NPCE) on the reinstatement and reconsolidation of cocaine-induced conditioned place preference (CPP) in male CD1 (ICR) mice, an approach not previously investigated. Methods: The extract was administered at a dose equivalent to 20 mg\/kg of CBD. Treatment significantly attenuated both priming- and stress-induced reinstatement of cocaine-induced CPP. Reinstatement was triggered either by a cocaine priming injection or by acute stress exposure, whereas reconsolidation-like processes were assessed by administering the extract following memory reactivation sessions and subsequently evaluating the persistence of cocaine-associated preference over time. Results: NPCE showed a consistent result with disruption of reconsolidation-like processes of cocaine-associated memory, with effects persisting for at least two weeks. The extract alone did not induce conditioned preference or aversion. Conclusions: These findings suggest that NPCE modulates drug-associated memory processes involved in relapse-like behavior. However, the underlying mechanisms were not directly evaluated and remain to be elucidated. Further studies are warranted to include both sexes, evaluate effects across multiple behavioral paradigms, directly compare full-spectrum extracts with isolated cannabinoids, and incorporate receptor-specific approaches to clarify the mechanisms of action.<\/jats:p>","DOI":"10.3390\/brainsci16060585","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T02:37:26Z","timestamp":1780454246000},"page":"585","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Non-Psychoactive Cannabis Extract Disrupts Reinstatement and Reconsolidation in Cocaine-Induced Conditioned Place Preference in Mice"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7393-3246","authenticated-orcid":false,"given":"Fabi\u00e1n Leonardo","family":"Barreto","sequence":"first","affiliation":[{"name":"Department of Pharmacy, National University of Colombia, Bogot\u00e1 14490, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7281-2946","authenticated-orcid":false,"given":"Mar\u00eda Constanza","family":"Lozano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National University of Colombia, Bogot\u00e1 14490, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9203-0829","authenticated-orcid":false,"given":"Yoshie Adriana","family":"Hata","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National University of Colombia, Bogot\u00e1 14490, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aura Rocio","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Faculty of Health and Society, Malm\u00f6 University, 205 06 Malm\u00f6, Sweden"},{"name":"Biofilms Research Center for Biointerfaces, Malm\u00f6 University, 205 06 Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5462-0630","authenticated-orcid":false,"given":"Jorge A.","family":"Mart\u00ednez-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National University of Colombia, Bogot\u00e1 14490, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Roque Bravo, R., Faria, A.C., Brito-da-Costa, A.M., Carmo, H., Mlad\u011bnka, P., Dias da Silva, D., and Remi\u00e3o, F. (2022). Cocaine: An updated overview on chemistry, detection, biokinetics, and pharmacotoxicological aspects including abuse pattern. Toxins, 14.","DOI":"10.3390\/toxins14040278"},{"key":"ref_2","unstructured":"UNODC (2024). World Drug Report 2024, United Nations Office on Drugs and Crime."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41401-018-0032-8","article-title":"Cannabidiol does not display drug abuse potential in mice behavior","volume":"40","author":"Navarrete","year":"2019","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107360","DOI":"10.1016\/j.addbeh.2022.107360","article-title":"Cannabidiol in the context of substance use disorder treatment: A systematic review","volume":"132","author":"Paulus","year":"2022","journal-title":"Addict. Behav."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"172982","DOI":"10.1016\/j.pbb.2020.172982","article-title":"Evaluation of the potential use of cannabidiol in the treatment of cocaine use disorder: A systematic review","volume":"196","author":"Rodrigues","year":"2020","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_6","first-page":"299","article-title":"Effects of cannabidiol on reward contextual memories induced by cocaine in male and female mice","volume":"36","author":"Iglesias","year":"2023","journal-title":"Acta Neuropsychiatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1177\/0269881120965952","article-title":"Cannabidiol prevents priming- and stress-induced reinstatement of the conditioned place preference induced by cocaine in mice","volume":"35","author":"Gasparyan","year":"2021","journal-title":"J. Psychopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"173065","DOI":"10.1016\/j.pbb.2020.173065","article-title":"Cannabidiol (CBD) reduces cocaine-environment memory in mice","volume":"199","author":"Chesworth","year":"2020","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1111\/adb.12366","article-title":"Cannabidiol disrupts the reconsolidation of contextual drug-associated memories in Wistar rats","volume":"22","author":"Takahashi","year":"2017","journal-title":"Addict. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"110390","DOI":"10.1016\/j.pnpbp.2021.110390","article-title":"Cannabidiol prevents several of the behavioral alterations related to cocaine addiction in mice","volume":"111","author":"Ledesma","year":"2021","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/j.1369-1600.2007.00070.x","article-title":"Measuring reward with the conditioned place preference (CPP) paradigm: Update of the last decade","volume":"12","author":"Tzschentke","year":"2007","journal-title":"Addict. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"McKendrick, G., and Graziane, N.M. (2020). Drug-induced conditioned place preference and its practical use in substance use disorder research. Front. Behav. Neurosci., 14.","DOI":"10.3389\/fnbeh.2020.582147"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1177\/0269881116667706","article-title":"Effects of an acute cannabidiol treatment on cocaine self-administration and cue-induced cocaine seeking in male rats","volume":"31","author":"Mahmud","year":"2017","journal-title":"J. Psychopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.bpsgos.2021.06.014","article-title":"Cannabidiol produces distinct U-shaped dose-response effects on cocaine-induced conditioned place preference","volume":"2","author":"Nedelescu","year":"2022","journal-title":"Biol. Psychiatry Glob. Open Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111014","DOI":"10.1016\/j.pnpbp.2024.111014","article-title":"Cannabidiol facilitates cocaine extinction and ameliorates cocaine-induced changes to the gut microbiome","volume":"133","author":"Chesworth","year":"2024","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112708","DOI":"10.1016\/j.biopha.2022.112708","article-title":"Cannabidiol decreases motivation for cocaine economics paradigm but does not prevent incubation of craving in mice","volume":"148","author":"Cantacorps","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1590\/1516-4446-2020-1416","article-title":"Cannabidiol for crack-cocaine craving","volume":"43","author":"Crippa","year":"2021","journal-title":"Braz. J. Psychiatry"},{"key":"ref_18","first-page":"2431","article-title":"Cannabidiol as a treatment for craving and relapse","volume":"116","author":"Brissette","year":"2021","journal-title":"Addiction"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"173376","DOI":"10.1016\/j.pbb.2022.173376","article-title":"Cannabidiol effects on cognition","volume":"216","author":"Rizkallah","year":"2022","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"109757","DOI":"10.1016\/j.drugalcdep.2022.109757","article-title":"Smoked cannabis reduces peak cocaine plasma levels","volume":"243","author":"Murray","year":"2023","journal-title":"Drug Alcohol Depend."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.addbeh.2017.04.006","article-title":"Intentional cannabis use to reduce crack cocaine use","volume":"72","author":"Kerr","year":"2017","journal-title":"Addict. Behav."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1080\/02791072.1999.10471776","article-title":"Therapeutic use of cannabis by crack addicts","volume":"31","author":"Labigalini","year":"1999","journal-title":"J. Psychoact. Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1124\/dmd.118.086074","article-title":"In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites","volume":"47","author":"Qian","year":"2019","journal-title":"Drug Metab. Dispos."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Russo, E.B. (2018). Cannabis therapeutics and the future of neurology. Front. Integr. Neurosci., 12.","DOI":"10.3389\/fnint.2018.00051"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115760","DOI":"10.1016\/j.biopha.2023.115760","article-title":"Cannabinoid type-2 receptors modulate terpene-induced anxiety","volume":"168","author":"Johnson","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_26","first-page":"285","article-title":"Appraising the entourage effect","volume":"157","author":"Tundidor","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.yebeh.2016.11.012","article-title":"Cannabinoids in treatment-resistant epilepsy","volume":"70","author":"Gloss","year":"2017","journal-title":"Epilepsy Behav."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1007\/s00213-004-1825-7","article-title":"Effects of low doses of THC and CBD","volume":"175","author":"Parker","year":"2004","journal-title":"Psychopharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"115048","DOI":"10.1016\/j.physbeh.2025.115048","article-title":"Non-psychoactive cannabis extract promotes extinction","volume":"301","author":"Barreto","year":"2025","journal-title":"Physiol. Behav."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., Dirnagl, U., and Emerson, M. (2020). Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000411"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.pnpbp.2018.01.002","article-title":"Modeling Cocaine Relapse in Rodents: Behavioral Considerations and Circuit Mechanisms","volume":"87","author":"Farrell","year":"2018","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"107740","DOI":"10.1016\/j.neuropharm.2019.107740","article-title":"Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT1A, and TRPV1 receptor mechanisms","volume":"167","author":"Galaj","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_33","first-page":"6481862","article-title":"Effects of cannabinoid exposure during adolescence on the conditioned rewarding effects of WIN 55,212-2 and cocaine in mice: Influence of the novelty-seeking trait","volume":"2016","author":"Vilanova","year":"2016","journal-title":"Neural Plast."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"577914","DOI":"10.1016\/j.jneuroim.2022.577914","article-title":"A three-compartment apparatus alters brain cytokines and neurotrophic factors in cocaine-induced CPP in mice","volume":"369","author":"Rosa","year":"2022","journal-title":"J. Neuroimmunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"151589","DOI":"10.1016\/j.acthis.2020.151589","article-title":"Neuroanatomical changes of the medial prefrontal cortex after prenatal and postnatal noise stress","volume":"122","author":"Teimouri","year":"2020","journal-title":"Acta Histochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s42238-024-00219-x","article-title":"Oral cannabis consumption and intraperitoneal THC:CBD dosing alter brain and plasma neurochemicals in mice","volume":"6","author":"Reisdorph","year":"2024","journal-title":"J. Cannabis Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.neuropharm.2004.08.009","article-title":"Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats","volume":"47","author":"Fadda","year":"2004","journal-title":"Neuropharmacology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1037\/0735-7044.109.1.71","article-title":"THC-induced place and taste aversions in Lewis and Sprague\u2013Dawley rats","volume":"109","author":"Parker","year":"1995","journal-title":"Behav. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"110462","DOI":"10.1016\/j.pnpbp.2021.110462","article-title":"CB1 receptor antagonist AM4113 reverts the effects of cannabidiol on cue- and stress-induced reinstatement of cocaine-seeking behaviour in mice","volume":"113","author":"Cantacorps","year":"2022","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"108913","DOI":"10.1016\/j.neuropharm.2021.108913","article-title":"Medial prefrontal cortex mechanisms of cannabidiol-induced aversive memory reconsolidation impairments","volume":"205","author":"Bayer","year":"2022","journal-title":"Neuropharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.neuron.2005.08.006","article-title":"Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory","volume":"47","author":"Miller","year":"2005","journal-title":"Neuron"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.pbb.2011.06.019","article-title":"Cannabinoid CB1 receptor antagonist rimonabant disrupts nicotine reward-associated memory in rats","volume":"99","author":"Fang","year":"2011","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"136634","DOI":"10.1016\/j.neulet.2022.136634","article-title":"Role of the cannabinoid CB1 receptor in methamphetamine-induced memory impairment","volume":"779","author":"Khodamoradi","year":"2022","journal-title":"Neurosci. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.neuropharm.2018.09.043","article-title":"Repeated cannabidiol treatment reduces cocaine intake and modulates neural proliferation and CB1R expression","volume":"143","author":"Valverde","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.bbr.2010.10.008","article-title":"Effects of cannabinoid CB1 receptor antagonist rimonabant on psychostimulant reward memory","volume":"217","author":"Yu","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.pnpbp.2019.01.017","article-title":"Modulation of stress- and cocaine prime-induced reinstatement through dopamine D3 receptor","volume":"92","author":"Hidalgo","year":"2019","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.conb.2013.01.022","article-title":"Addiction: A drug-induced disorder of memory reconsolidation","volume":"23","author":"Tronson","year":"2013","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neubiorev.2018.09.008","article-title":"Addiction and stress: An allostatic view","volume":"106","author":"Koob","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.physbeh.2019.01.022","article-title":"The role of stress in drug addiction: An integrative review","volume":"202","author":"Ruisoto","year":"2019","journal-title":"Physiol. Behav."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0165-0173(00)00024-2","article-title":"Stress-induced relapse to heroin and cocaine seeking in rats: A review","volume":"33","author":"Shaham","year":"2000","journal-title":"Brain Res. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"135555","DOI":"10.1016\/j.neulet.2020.135555","article-title":"Role of 5-HT1A receptor-mediated transmission in stress-induced cocaine memory","volume":"743","author":"Chu","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/j.pain.0000000000001386","article-title":"Cannabidiol modulates serotonergic transmission and reverses allodynia and anxiety-like behavior","volume":"160","author":"McLaughlin","year":"2019","journal-title":"Pain"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"137723","DOI":"10.1016\/j.neulet.2024.137723","article-title":"Cannabidiol exhibits anxiolytic- and antipsychotic-like effects in mice","volume":"826","author":"Shu","year":"2024","journal-title":"Neurosci. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Jenkins, B.W., Spina, H.A., Nicholson, K., Newman, A.E.M., and Khokhar, J.Y. (2024). Cannabidiol (CBD) potentiates physiological and behavioral markers of HPA axis responsivity. bioRxiv.","DOI":"10.1101\/2024.10.17.618869"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Cservenka, A., Lahanas, S., and Dotson-Bossert, J. (2018). Marijuana use and HPA axis functioning in humans. Front. Psychiatry, 9.","DOI":"10.3389\/fpsyt.2018.00472"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.psychres.2013.12.016","article-title":"Flattened cortisol awakening response in schizophrenia after cannabis exposure","volume":"215","author":"Monteleone","year":"2014","journal-title":"Psychiatry Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.expneurol.2014.01.022","article-title":"Sex differences in the neurobiology of drug addiction","volume":"259","author":"Bobzean","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/S0006-8993(03)02346-1","article-title":"Sex differences in the conditioned rewarding effects of cocaine","volume":"970","author":"Russo","year":"2003","journal-title":"Brain Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1002\/j.2040-4603.2014.tb00575.x","article-title":"Sex differences in the HPA axis","volume":"4","author":"Goel","year":"2014","journal-title":"Compr. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/npp.2017.140","article-title":"Sex-dependent effects of cannabis and cannabinoids: A translational perspective","volume":"43","author":"Cooper","year":"2018","journal-title":"Neuropsychopharmacology"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/6\/585\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T03:40:18Z","timestamp":1780458018000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/6\/585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":60,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["brainsci16060585"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16060585","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]}}}