{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:35:26Z","timestamp":1790642126666,"version":"4.1.0"},"reference-count":98,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T00:00:00Z","timestamp":1608768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["DA000633-01"],"award-info":[{"award-number":["DA000633-01"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness. Since the legalization of cannabis and the approval of cannabidiol (CBD) by the US Food and Drug Administration, therapeutic potential of CBD for the treatment of SUDs and other diseases has been widely explored. In this mini-review article, we first review the history and evidence supporting CBD as a potential pharmacotherapeutic. We then focus on recent progress in preclinical research regarding the pharmacological efficacy of CBD and the underlying receptor mechanisms on addictive-like behavior. Growing evidence indicates that CBD has therapeutic potential in reducing drug reward, as assessed in intravenous drug self-administration, conditioned place preference and intracranial brain-stimulation reward paradigms. In addition, CBD is effective in reducing relapse in experimental animals. Both in vivo and in vitro receptor mechanism studies indicate that CBD may act as a negative allosteric modulator of type 1 cannabinoid (CB1) receptor and an agonist of type 2 cannabinoid (CB2), transient receptor potential vanilloid 1 (TRPV1), and serotonin 5-HT1A receptors. Through these multiple-receptor mechanisms, CBD is believed to modulate brain dopamine in response to drugs of abuse, leading to attenuation of drug-taking and drug-seeking behavior. While these findings suggest that CBD is a promising therapeutic candidate, further investigation is required to verify its safety, pharmacological efficacy and the underlying receptor mechanisms in both experimental animals and humans.<\/jats:p>","DOI":"10.3390\/ijms22010134","type":"journal-article","created":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T22:56:45Z","timestamp":1608850605000},"page":"134","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Possible Receptor Mechanisms Underlying Cannabidiol Effects on Addictive-like Behaviors in Experimental Animals"],"prefix":"10.3390","volume":"22","author":[{"given":"Ewa","family":"Galaj","sequence":"first","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6482-8104","authenticated-orcid":false,"given":"Zheng-Xiong","family":"Xi","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/BF02862859","article-title":"An archaeological and historical account of cannabis in China","volume":"28","author":"Li","year":"1973","journal-title":"Econ. Bot."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1590\/S1516-44462006000200015","article-title":"History of cannabis as a medicine: A review","volume":"28","author":"Zuardi","year":"2006","journal-title":"Braz. J. Psychiatr."},{"key":"ref_3","first-page":"34","article-title":"Marijuana in medicine: Past, present and future","volume":"110","author":"Mikuriya","year":"1969","journal-title":"Calif. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1080\/02791072.1981.10471447","article-title":"The religious and medicinal uses of cannabis in China, India and Tibet","volume":"13","author":"Touw","year":"1981","journal-title":"J. Psychoact. Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1310\/hpj4806-473","article-title":"The federal controlled substances act: Schedules and pharmacy Registration","volume":"48","author":"Gabay","year":"2013","journal-title":"Hosp. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1021\/ja01062a046","article-title":"Isolation, structure, and partial synthesis of an active constituent of hashish","volume":"86","author":"Gaoni","year":"1964","journal-title":"J. Am. Chem. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1038\/sj.ijo.0803272","article-title":"The pharmacology of cannabinoid receptors and their ligands: An overview","volume":"30","author":"Pertwee","year":"2006","journal-title":"Int. J. Obes."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1126\/science.169.3945.611","article-title":"Chemical basis of hashish activity","volume":"169","author":"Mechoulam","year":"1970","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1159\/000137430","article-title":"Chronic administration of cannabidiol to healthy volunteers and epileptic patients","volume":"21","author":"Cunha","year":"1980","journal-title":"Pharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1111\/epi.12610","article-title":"The case for medical marijuana in epilepsy","volume":"55","author":"Maa","year":"2014","journal-title":"Epilepsia"},{"key":"ref_11","unstructured":"(2020, December 24). FDA EPIDIOLEX (Cannabidiol) Oral Solution, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2018\/210365lbl.pdf."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/j.bmc.2015.01.059","article-title":"Cannabidiol (CBD) and its analogs: A review of their effects on inflammation","volume":"23","author":"Burstein","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-neuro-070815-014038","article-title":"Beyond the CB1 receptor: Is cannabidiol the answer for disorders of motivation?","volume":"39","author":"Zlebnik","year":"2016","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"91","DOI":"10.4103\/sni.sni_45_18","article-title":"Review of the neurological benefits of phytocannabinoids","volume":"9","author":"Maroon","year":"2018","journal-title":"Surg. Neurol. Int."},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1017\/S2045796018000239","article-title":"Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: A critical overview","volume":"27","author":"Mandolini","year":"2018","journal-title":"Epidemiol. Psychiatr. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Calpe-L\u00f3pez, C., Garc\u00eda-Pardo, M.P., and Aguilar, M.A. (2019). Cannabidiol treatment might promote resilience to cocaine and methamphetamine use disorders: A review of possible mechanisms. Molecules, 24.","DOI":"10.3390\/molecules24142583"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chye, Y., Christensen, E., Solowij, N., and Y\u00fccel, M. (2019). The endocannabinoid system and cannabidiol\u2019s promise for the treatment of substance use disorder. Front. Psychiatr., 10.","DOI":"10.3389\/fpsyt.2019.00063"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/bs.pmbts.2019.06.005","article-title":"Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings","volume":"167","author":"Elsaid","year":"2019","journal-title":"Prog. Mol. Biol. Transl. Sci"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rodrigues, L.A., Caroba, M.E.S., Taba, F.K., Filev, R., and Gallassi, A.D. (2020). Evaluation of the potential use of cannabidiol in the treatment of cocaine use disorder: A systematic review. Pharmacol. Biochem. Behav., 196.","DOI":"10.1016\/j.pbb.2020.172982"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1007\/s13311-015-0373-7","article-title":"Early phase in the development of cannabidiol as a treatment for addiction: Opioid relapse takes initial center stage","volume":"12","author":"Hurd","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_22","first-page":"33","article-title":"Cannabidiol as an Intervention for Addictive Behaviors: A systematic review of the evidence","volume":"9","author":"Cata","year":"2015","journal-title":"Subst. Abus."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.neubiorev.2019.09.036","article-title":"How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review","volume":"107","author":"Freeman","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1111\/acer.13964","article-title":"Cannabidiol as a novel candidate alcohol use disorder pharmacotherapy: A systematic review","volume":"43","author":"Turna","year":"2019","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1037\/pha0000272","article-title":"Effects of cannabidiol on alcohol-related outcomes: A review of preclinical and human research","volume":"27","author":"Nona","year":"2019","journal-title":"Exp. Clin. Psychopharmacol."},{"key":"ref_26","first-page":"185","article-title":"Differential effect of cannabinol and cannabidiol on THC-induced responses during abstinence in morphine-dependent rats","volume":"12","author":"Hine","year":"1975","journal-title":"Res. Commun. Chem. Pathol. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/0024-3205(75)90435-X","article-title":"Interactions between cannabidiol and \u03949-THC during abstinence in morphine-dependent rats","volume":"17","author":"Hine","year":"1975","journal-title":"Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/BF00426828","article-title":"Effect of some cannabinoids on naloxone-precipitated abstinence in morphine-dependent mice","volume":"49","author":"Bhargava","year":"1976","journal-title":"Psychopharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"14764","DOI":"10.1523\/JNEUROSCI.4291-09.2009","article-title":"Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances","volume":"29","author":"Ren","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1055\/s-0043-117838","article-title":"Effects of cannabidiol on morphine conditioned place preference in mice","volume":"84","author":"Markos","year":"2018","journal-title":"Planta Med."},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s00213-010-1887-7","article-title":"Role of serotonin 5-HT2A and 5-HT2C receptors on brain stimulation reward and the reward-facilitating effect of cocaine","volume":"213","author":"Katsidoni","year":"2011","journal-title":"Psychopharmacology"},{"key":"ref_33","first-page":"35","article-title":"Cocaine N-demethylation and the metabolism-related hepatotoxicity can be prevented by cytochrome P450 3A inhibitors","volume":"270","author":"Pellinen","year":"1994","journal-title":"Eur. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1006\/taap.1998.8403","article-title":"Effect of cytochrome P450 inducers on cocaine-mediated hepatotoxicity","volume":"150","author":"Bornheim","year":"1998","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_35","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_36","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 in the mouse hippocampus","volume":"143","author":"Valverde","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Galaj, E., Bi, G.-H., Yang, H.-J., and Xi, Z.-X. (2020). Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT1A and TRPV1 receptor mechanisms. Neuropharmacology, 167.","DOI":"10.1016\/j.neuropharm.2019.107740"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1007\/s00213-004-1825-7","article-title":"Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats","volume":"175","author":"Parker","year":"2004","journal-title":"Psychopharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1038\/sj.npp.1301648","article-title":"Context-specific reversal of cocaine sensitization by the CB1 cannabinoid receptor antagonist rimonabant","volume":"33","author":"Gerdeman","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1038\/s41386-018-0050-8","article-title":"Unique treatment potential of cannabidiol for the prevention of relapse to drug use: Preclinical proof of principle","volume":"43","author":"Kerr","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/sj.bjp.0707133","article-title":"Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro","volume":"150","author":"Thomas","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1111\/bph.14440","article-title":"Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors","volume":"176","author":"Tham","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1111\/bph.13250","article-title":"Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor","volume":"172","author":"Laprairie","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Pinilla, E., Varani, K., Reyes-Resina, I., Angelats, E., Vincenzi, F., Ferreiro-Vera, C., Oyarzabal, J., Canela, E.I., Lanciego, J.L., and Nadal, X. (2017). Binding and Signaling Studies Disclose a Potential Allosteric Site for Cannabidiol in Cannabinoid CB2 Receptors. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00744"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e920","DOI":"10.1038\/tp.2016.195","article-title":"Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose","volume":"6","author":"Seeman","year":"2016","journal-title":"Transl. Psychiatry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/sj.bjp.0704327","article-title":"Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide","volume":"134","author":"Bisogno","year":"2001","journal-title":"Br. J. Pharmacology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8711","DOI":"10.1074\/jbc.M114.618447","article-title":"Fatty acid-binding proteins (FABPs) are intracellular carriers for \u03949-tetrahydrocannabinol (THC) and cannabidiol (CBD)","volume":"290","author":"Elmes","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1007\/s11064-005-6978-1","article-title":"Agonistic Properties of cannabidiol at 5-HT1a receptors","volume":"30","author":"Russo","year":"2005","journal-title":"Neurochem. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/sj.bjp.0707442","article-title":"The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: \u03949-tetrahydrocannabinol, cannabidiol and \u03949-tetrahydrocannabivarin","volume":"153","author":"Pertwee","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1007\/s00210-006-0033-x","article-title":"Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors","volume":"372","author":"Kathmann","year":"2006","journal-title":"Naunyn. Schmied. Arch. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.phrs.2015.07.017","article-title":"Aiming for allosterism: Evaluation of allosteric modulators of CB1 in a neuronal model","volume":"99","author":"Straiker","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Bi, G.-H., Galaj, E., He, Y., and Xi, Z.-X. (2019). Cannabidiol inhibits sucrose self-administration by CB1 and CB2 receptor mechanisms in rodents. Addict. Biol., e12783.","DOI":"10.1111\/adb.12783"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1038\/sj.npp.1301552","article-title":"Cannabinoid CB1 receptor antagonists attenuate cocaine\u2019s rewarding effects: Experiments with self-administration and brain-stimulation reward in rats","volume":"33","author":"Xi","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1097\/FBP.0b013e32833b33c5","article-title":"Cannabidiol inhibitory effect on marble-burying behaviour: Involvement of CB1 receptors","volume":"21","author":"Casarotto","year":"2010","journal-title":"Behav. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.euroneuro.2004.04.003","article-title":"Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization","volume":"15","author":"Lesscher","year":"2005","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_56","first-page":"806","article-title":"Involvement of cannabinoid CB1 receptors in drug addiction: Effects of rimonabant on behavioral responses induced by cocaine","volume":"58","author":"Filip","year":"2006","journal-title":"Pharmacol. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.brainres.2012.01.030","article-title":"The effects of cannabinoid CB1, CB2 and vanilloid TRPV1 receptor antagonists on cocaine addictive behavior in rats","volume":"1444","author":"Adamczyk","year":"2012","journal-title":"Brain Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Thapa, D., Toguri, J.T., Szczesniak, A.M., and Kelly, M.E. (2017). The Non-psychoactive phytocannabinoid, cannabidiol (CBD), and the synthetic derivatives, HU308 and CBD-DMH, reduces hyperalgesia and inflammation in a mouse model of corneal injury. FASEB J., 31.","DOI":"10.1096\/fasebj.31.1_supplement.811.7"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/j.pain.0000000000001386","article-title":"Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain","volume":"160","author":"McLaughlin","year":"2019","journal-title":"Pain"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.bcp.2018.08.046","article-title":"Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes","volume":"157","author":"Navarro","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/syn.20714","article-title":"A nonsynonymous polymorphism in cannabinoid CB2 receptor gene is associated with eating disorders in humans and food intake is modified in mice by its ligands","volume":"64","author":"Ishiguro","year":"2010","journal-title":"Synapse"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.neulet.2010.12.031","article-title":"Cannabidiol decreases body weight gain in rats: Involvement of CB2 receptors","volume":"490","author":"Jankowski","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Deveaux, V., Cadoudal, T., Ichigotani, Y., Teixeira-Clerc, F., Louvet, A., Manin, S., Nhieu, J.T.-V., Belot, M.P., Zimmer, A., and Even, P. (2009). Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005844"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.nbd.2009.10.023","article-title":"The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors","volume":"37","author":"Castillo","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.neuro.2015.08.007","article-title":"Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release","volume":"50","author":"Gobira","year":"2015","journal-title":"Neurotoxicology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"109637","DOI":"10.1016\/j.pnpbp.2019.109637","article-title":"Cannabidiol attenuates aggressive behavior induced by social isolation in mice: Involvement of 5-HT1A and CB1 receptors","volume":"94","author":"Hartmann","year":"2019","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"E5007","DOI":"10.1073\/pnas.1413210111","article-title":"Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice","volume":"111","author":"Zhang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1111\/adb.12367","article-title":"Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons in rats","volume":"22","author":"Zhang","year":"2017","journal-title":"Addict. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1089\/can.2019.0028","article-title":"Anticonvulsive properties of cannabidiol in a model of generalized seizure are transient receptor potential vanilloid 1 dependent","volume":"5","author":"Gray","year":"2020","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1038\/npp.2015.268","article-title":"5-HT1A autoreceptors in the dorsal raphe nucleus convey vulnerability to compulsive cocaine seeking","volume":"41","author":"You","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1038\/npp.2016.93","article-title":"Cannabidiol modulates fear memory formation through interactions with serotonergic transmission in the mesolimbic system","volume":"41","author":"Norris","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3369","DOI":"10.1111\/bph.14380","article-title":"Effects of cannabidiol plus naltrexone on motivation and ethanol consumption","volume":"175","author":"Manzanares","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.neubiorev.2018.12.026","article-title":"Progress in brain cannabinoid CB2 receptors: From gene to behavior","volume":"98","author":"Jordan","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.bcp.2018.09.013","article-title":"Role of the endocannabinoid system in drug addiction","volume":"157","author":"Manzanares","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1038\/npp.2012.22","article-title":"Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB2 receptors","volume":"37","author":"Trigo","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/j.neuron.2016.08.017","article-title":"Antipsychotic-like effects of M4 positive allosteric modulators are mediated by CB2 receptor-dependent inhibition of dopamine release","volume":"91","author":"Foster","year":"2016","journal-title":"Neuron"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"5160","DOI":"10.1523\/JNEUROSCI.3387-15.2016","article-title":"Cannabidiol counteracts amphetamine-induced neuronal and behavioral sensitization of the mesolimbic dopamine pathway through a novel mTOR\/p70S6 kinase signaling pathway","volume":"36","author":"Renard","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1021\/cn5000524","article-title":"Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: Potential for the treatment of neuronal hyperexcitability","volume":"5","author":"Iannotti","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1111\/j.1476-5381.2010.01166.x","article-title":"Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes","volume":"163","author":"Ligresti","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_80","first-page":"77","article-title":"TRPV1 in the central nervous system: Synaptic plasticity, function, and pharmacological implications","volume":"68","author":"Edwards","year":"2014","journal-title":"Prog. Drug Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1517\/17460441.2013.780021","article-title":"Latest advances in the discovery of fatty acid amide hydrolase inhibitors","volume":"8","author":"Bisogno","year":"2013","journal-title":"Exp. Opin. Drug Discov."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.pbb.2005.02.015","article-title":"The role of endocannabinoid transmission in cocaine addiction","volume":"81","author":"Arnold","year":"2005","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1196\/annals.1432.056","article-title":"An endocannabinoid hypothesis of drug reward and drug addiction","volume":"1139","author":"Onaivi","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1177\/0269881118799954","article-title":"Cannabidiol treatment reduces the motivation to self-administer methamphetamine and methamphetamine-primed relapse in rats","volume":"32","author":"Hay","year":"2018","journal-title":"J. Psychopharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.pnpbp.2017.08.022","article-title":"Cannabidiol inhibits priming-induced reinstatement of methamphetamine in REM sleep deprived rats","volume":"82","author":"Haghparast","year":"2018","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1093\/toxres\/tfaa021","article-title":"Cannabidiol attenuates methamphetamine-induced conditioned place preference via the Sigma1R\/AKT\/GSK-3\u03b2\/CREB signaling pathway in rats","volume":"9","author":"Yang","year":"2020","journal-title":"Toxicol. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e12740","DOI":"10.1111\/adb.12740","article-title":"Cannabidiol modulates the expression of neuroinflammatory factors in stress- and drug-induced reinstatement of methamphetamine in extinguished rats","volume":"25","author":"Dargahi","year":"2020","journal-title":"Addict. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1016\/0024-3205(90)90309-F","article-title":"Interleukin-1 stimulates catecholamine release from the hypothalamus","volume":"47","author":"Palazzolo","year":"1990","journal-title":"Life Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3574","DOI":"10.1523\/JNEUROSCI.13-08-03574.1993","article-title":"Interleukin-1 beta augments release of norepinephrine, dopamine, and serotonin in the rat anterior hypothalamus","volume":"13","author":"Shintani","year":"1993","journal-title":"J. Neurosci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jns.2013.06.001","article-title":"Direct effects of secretory products of immune cells on neurons and glia","volume":"333","author":"Benjamins","year":"2013","journal-title":"J. Neurolog. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3622","DOI":"10.1021\/acschemneuro.9b00225","article-title":"Methamphetamine activates toll-like receptor 4 to induce central immune signaling within the ventral tegmental area and contributes to extracellular dopamine increase in the nucleus accumbens shell","volume":"10","author":"Wang","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1111\/adb.12495","article-title":"Cannabidiol reduces ethanol consumption, motivation and relapse in mice","volume":"23","author":"Navarrete","year":"2018","journal-title":"Addict. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e12765","DOI":"10.1111\/adb.12765","article-title":"Gender differences in the effects of cannabidiol on ethanol binge drinking in mice","volume":"25","author":"Manzanares","year":"2020","journal-title":"Addict. Biol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.alcohol.2017.06.004","article-title":"THC inhibits the expression of ethanol-induced locomotor sensitization in mice","volume":"65","author":"Filev","year":"2017","journal-title":"Alcohol"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1007\/s40263-019-00664-w","article-title":"Potential of cannabinoid receptor ligands as treatment for substance use disorders","volume":"33","author":"Galaj","year":"2019","journal-title":"CNS Drugs"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e00682","DOI":"10.1002\/prp2.682","article-title":"Diversity of molecular targets and signaling pathways for CBD","volume":"8","author":"Devi","year":"2020","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.tips.2009.07.006","article-title":"Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb","volume":"30","author":"Izzo","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1038\/sj.bjp.0707460","article-title":"The orphan receptor GPR55 is a novel cannabinoid receptor","volume":"152","author":"Ryberg","year":"2007","journal-title":"Br. J. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/134\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:45:57Z","timestamp":1760179557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/134"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,24]]},"references-count":98,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22010134"],"URL":"https:\/\/doi.org\/10.3390\/ijms22010134","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,24]]}}}