Introduction: An altered neurodevelopmental trajectory associated with prenatal exposure to ∆-9-tetrahydrocannabinol (THC) leads to aberrant cognitive processing through a perturbation in the effectors of hippocampal plasticity in the juvenile offspring. As adolescence presents a unique window of opportunity for "brain reprogramming", we aimed at assessing the role of the non-psychoactive phytocannabinoid cannabidiol (CBD) as a rescue strategy to temper prenatal THC-induced harm. Methods: To this aim, Wistar rats prenatally exposed to THC (2 mg/kg s.c.) or vehicle (gestational days 5-20) were tested for specific indexes of spatial and configural memory in the reinforcement-motivated Can test and in the aversion-driven Barnes maze test during adolescence. Markers of hippocampal excitatory plasticity and endocannabinoid signaling-NMDAR subunits NR1 and 2A-, mGluR5-, and their respective scaffold proteins PSD95- and Homer 1-; CB1R- and the neuromodulatory protein HINT1 mRNA levels were evaluated. CBD (40 mg/kg i.p.) was administered to the adolescent offspring before the cognitive tasks. Results: The present results show that prenatal THC impairs hippocampal memory functions and the underlying synaptic plasticity; CBD is able to mitigate cognitive impairment in both reinforcement- and aversion-related tasks and the neuroadaptation of hippocampal excitatory synapses and CB1R-related signaling. Discussion: While this research shows CBD potential in dampening prenatal THC-induced consequences, we point out the urgency to curb cannabis use during pregnancy in order to avoid detrimental bio-behavioral outcomes in the offspring.

Department of Biological Chemical and Pharmaceutical Sciences and Technologies and ATEN Center University of Palermo Palermo Italy

Department of Biomedicine Neuroscience and Advanced Diagnostics University of Palermo Palermo Italy

Department of Health Promotion Mother and Child Care Internal Medicine and Medical Specialties of Excellence G D'Alessandro University of Palermo Palermo Italy

Fondazione Policlinico Universitario A Gemelli IRCSS Rome Italy

Forensic Laboratory of Biologically Active Compounds Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague Czechia

Pharmacology Section Department of Healthcare Surveillance and Bioethics Università Cattolica del Sacro Cuore Rome Italy

Psychedelics Research Centre National Institute of Mental Health Prague Czechia

Zobrazit více v PubMed

Alalawi A., Dodu J. C., Woolley-Roberts M., Brodie J., Di Marzo V., Soderstrom K. (2019). Cannabidiol improves vocal learning-dependent recovery from, and reduces magnitude of deficits following, damage to a cortical-like brain region in a songbird pre-clinical animal model. Neuropharmacology 158, 107716. 10.1016/j.neuropharm.2019.107716 PubMed DOI

Anderson L. L., Udoh M., Everett-Morgan D., Heblinski M., McGregor I. S., Banister S. D., et al. (2022). Olivetolic acid, a cannabinoid precursor in Cannabis sativa, but not CBGA methyl ester exhibits a modest anticonvulsant effect in a mouse model of Dravet syndrome. J. cannabis Res. 4 (1), 2. 10.1186/s42238-021-00113-w PubMed DOI PMC

Aso E., Fernández-Dueñas V., López-Cano M., Taura J., Watanabe M., Ferrer I., et al. (2019). Adenosine a2a-cannabinoid CB1 receptor heteromers in the Hippocampus: Cannabidiol blunts d9-tetrahydrocannabinol-induced cognitive impairment. Mol. Neurobiol. 56 (8), 5382–5391. 10.1007/s12035-018-1456-3 PubMed DOI

Aychman M. M., Goldman D. L., Kaplan J. S. (2023). Cannabidiol's neuroprotective properties and potential treatment of traumatic brain injuries. Front. neurology 14, 1087011. 10.3389/fneur.2023.1087011 PubMed DOI PMC

Bannerman D., Sprengel R., Sanderson D., McHugh S. B., Rawlins J. N. P., Monyer H., et al. (2014). Hippocampal synaptic plasticity, spatial memory and anxiety. Nat. Rev. Neurosci. 15, 181–192. 10.1038/nrn3677 PubMed DOI

Bara A., Ferland J. N., Rompala G., Szutorisz H., Hurd Y. L. (2021). Cannabis and synaptic reprogramming of the developing brain. Nat. Rev. Neurosci. 22 (7), 423–438. 10.1038/s41583-021-00465-5 PubMed DOI PMC

Basavarajappa B. S., Nixon R. A., Arancio O. (2009). Endocannabinoid system: Emerging role from neurodevelopment to neurodegeneration. Mini Rev. Med. Chem. 9 (4), 448–462. 10.2174/138955709787847921 PubMed DOI PMC

Bateup H. S., Johnson C. A., Denefrio C. L., Saulnier J. L., Kornacker K., Sabatini B. L. (2013). Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron 78 (3), 510–522. 10.1016/j.neuron.2013.03.017 PubMed DOI PMC

Batista E. M., Doria J. G., Ferreira-Vieira T. H., Alves-Silva J., Ferguson S. S., Moreira F. A., et al. (2016). Orchestrated activation of mGluR5 and CB1 promotes neuroprotection. Mol. brain 9 (1), 80. 10.1186/s13041-016-0259-6 PubMed DOI PMC

Bhattacharyya S., Morrison P. D., Fusar-Poli P., Martin-Santos R., Borgwardt S., Winton-Brown T., et al. (2010). Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacol. official Publ. Am. Coll. Neuropsychopharmacol. 35 (3), 764–774. 10.1038/npp.2009.184 PubMed DOI PMC

Bhunia S., Kolishetti N., Arias A. Y., Vashist A., Nair M. (2022). Cannabidiol for neurodegenerative disorders: A comprehensive review. Front. Pharmacol. 13, 989717. 10.3389/fphar.2022.989717 PubMed DOI PMC

Bilge S., Ekici B. (2021). CBD-Enriched cannabis for autism spectrum disorder: An experience of a single center in Turkey and reviews of the literature. J. cannabis Res. 3 (1), 53. 10.1186/s42238-021-00108-7 PubMed DOI PMC

Bisogno T., Hanus L., De Petrocellis L., Tchilibon S., Ponde D. E., Brandi I., et al. (2001). Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br. J. Pharmacol. 134 (4), 845–852. 10.1038/sj.bjp.0704327 PubMed DOI PMC

Blessing E. M., Steenkamp M. M., Manzanares J., Marmar C. R. (2015). Cannabidiol as a potential treatment for anxiety disorders. Neurother. J. Am. Soc. Exp. Neurother. 12 (4), 825–836. 10.1007/s13311-015-0387-1 PubMed DOI PMC

Bonansco C., Fuenzalida M. (2016). Plasticity of hippocampal excitatory-inhibitory balance: Missing the synaptic control in the epileptic brain. Neural plast. 2016, 8607038. 10.1155/2016/8607038 PubMed DOI PMC

Boyaji S., Merkow J., Elman R. N. M., Kaye A. D., Yong R. J., Urman R. D. (2020). The role of cannabidiol (CBD) in chronic pain management: An assessment of current evidence. Curr. pain headache Rep. 24 (2), 4. 10.1007/s11916-020-0835-4 PubMed DOI

Brancato A., Cannizzaro C. (2018). Mothering under the influence: how perinatal drugs of abuse alter the mother-infant interaction. Reviews in the Neurosciences, 29(3), 283–294. 10.1515/revneuro-2017-0052 PubMed DOI

Brancato A., Castelli V., Lavanco G., Tringali G., Micale V., Kuchar M., D'Amico C., Pizzolanti G., Feo S., Cannizzaro C. (2021). Binge-like alcohol exposure in adolescence: Behavioural, neuroendocrine and molecular evidence of abnormal neuroplasticity… and return, and return. Biomedicines, 9(9), 1161. 10.3390/biomedicines9091161 PubMed DOI PMC

Brancato A., Castelli V., Lavanco G., Cannizzaro C. (2020a). Environmental enrichment during adolescence mitigates cognitive deficits and alcohol vulnerability due to continuous and intermittent perinatal alcohol exposure in adult rats. Front. Behav. Neurosci. 14, 583122. 10.3389/fnbeh.2020.583122 PubMed DOI PMC

Brancato A., Castelli V., Lavanco G., Marino R. A. M., Cannizzaro C. (2020b). In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?. J. Psychopharmacol. Oxf. Engl. 34 (6), 663–679. 10.1177/0269881120916135 PubMed DOI

Brancato A., Lavanco G., Cavallaro A., Plescia F., Cannizzaro C. (2016). The use of the Emotional-Object Recognition as an assay to assess learning and memory associated to an aversive stimulus in rodents. J. Neurosci. methods 274, 106–115. 10.1016/j.jneumeth.2016.09.010 PubMed DOI

Broyd S. J., van Hell H. H., Beale C., Yücel M., Solowij N. (2016). Acute and chronic effects of cannabinoids on human cognition-A systematic review. Biol. psychiatry 79 (7), 557–567. 10.1016/j.biopsych.2015.12.002 PubMed DOI

Busquets-Garcia A., Bains J., Marsicano G. (2018). CB1 receptor signaling in the brain: Extracting specificity from ubiquity. Neuropsychopharmacology 43, 4–20. 10.1038/npp.2017.206 PubMed DOI PMC

Campos A. C., Brant F., Miranda A. S., Machado F. S., Teixeira A. L. (2015). Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria. Neuroscience 289, 166–180. 10.1016/j.neuroscience.2014.12.051 PubMed DOI

Castelli V., Brancato A., Cavallaro A., Lavanco G., Cannizzaro C. (2017). Homer2 and alcohol: A mutual interaction. Front. psychiatry 8, 268. 10.3389/fpsyt.2017.00268 PubMed DOI PMC

Castelli V., Lavanco G., Feo S., D'Amico C., Micale V., Kuchar M., et al. (2023). Prenatal exposure to d9-tetrahydrocannabinol affects hippocampus-related cognitive functions in the adolescent rat offspring: Focus on specific markers of neuroplasticity. Pharmaceutics 15 (2), 692. 10.3390/pharmaceutics15020692 PubMed DOI PMC

Castelli V., Plescia F., Maniaci G., Lavanco G., Pizzolanti G., Brancato A., et al. (2022). Alcohol binge drinking in adolescence and psychological profile: Can the preclinical model crack the chicken-or-egg question?. Front. psychiatry 13, 996965. 10.3389/fpsyt.2022.996965 PubMed DOI PMC

Castillo-Arellano J., Canseco-Alba A., Cutler S. J., León F. (2023). The polypharmacological effects of cannabidiol. Mol. (Basel, Switz. 28 (7), 3271. 10.3390/molecules28073271 PubMed DOI PMC

Chagas M. H., Crippa J. A., Zuardi A. W., Hallak J. E., Machado-de-Sousa J. P., Hirotsu C., et al. (2013). Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats. J. Psychopharmacol. Oxf. Engl. 27 (3), 312–316. 10.1177/0269881112474524 PubMed DOI

Chan H. W., McKirdy N. C., Peiris H. N., Rice G. E., Mitchell M. D. (2013). The role of endocannabinoids in pregnancy. Reprod. Camb. Engl. 146 (3), R101–R109. 10.1530/REP-12-0508 PubMed DOI

Chávez A. E., Chiu C. Q., Castillo P. E. (2010). TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nat. Neurosci. 13 (12), 1511–1518. 10.1038/nn.2684 PubMed DOI PMC

Chomczynski P., Sacchi N. (2006). The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: Twenty-something years on. Nat. Protoc. 1 (2), 581–585. 10.1038/nprot.2006.83 PubMed DOI

Crippa J. A., Guimarães F. S., Campos A. C., Zuardi A. W. (2018). Translational investigation of the therapeutic potential of cannabidiol (CBD): Toward a new age. Front. Immunol. 9, 2009. 10.3389/fimmu.2018.02009 PubMed DOI PMC

D'Souza D. C., Perry E., MacDougall L., Ammerman Y., Cooper T., Wu Y. T., et al. (2004). The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: Implications for psychosis. Neuropsychopharmacology 29 (8), 1558–1572. 10.1038/sj.npp.1300496 PubMed DOI

De Felice M., Laviolette S. R. (2021). Reversing the psychiatric effects of neurodevelopmental cannabinoid exposure: Exploring pharmacotherapeutic interventions for symptom improvement. Int. J. Mol. Sci. 22 (15), 7861. 10.3390/ijms22157861 PubMed DOI PMC

De Gregorio D., McLaughlin R. J., Posa L., Ochoa-Sanchez R., Enns J., Lopez-Canul M., et al. (2019). Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain 160 (1), 136–150. 10.1097/j.pain.0000000000001386 PubMed DOI PMC

de Salas-Quiroga A., Díaz-Alonso J., García-Rincón D., Remmers F., Vega D., Gómez-Cañas M., et al. (2015). Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons. Proc. Natl. Acad. Sci. U. S. A. 112 (44), 13693–13698. 10.1073/pnas.1514962112 PubMed DOI PMC

de Salas-Quiroga A., García-Rincón D., Gómez-Domínguez D., Valero M., Simón-Sánchez S., Paraíso-Luna J., et al. (2020). Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure. Neuropsychopharmacol 45, 877–886. 10.1038/s41386-020-0621-3 PubMed DOI PMC

Drazanova E., Ruda-Kucerova J., Kratka L., Stark T., Kuchar M., Maryska M., et al. (2019). Different effects of prenatal MAM vs. perinatal THC exposure on regional cerebral blood perfusion detected by Arterial Spin Labelling MRI in rats. Sci. Rep. 9 (1), 6062. 10.1038/s41598-019-42532-z PubMed DOI PMC

Esposito G., Scuderi C., Valenza M., Togna G. I., Latina V., De Filippis D., et al. (2011). Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PloS one 6 (12), e28668. 10.1371/journal.pone.0028668 PubMed DOI PMC

Etemad L., Karimi G., Alavi M. S., Roohbakhsh A. (2022). Pharmacological effects of cannabidiol by transient receptor potential channels. Life Sci. 300, 120582. 10.1016/j.lfs.2022.120582 PubMed DOI

Fagherazzi E. V., Garcia V. A., Maurmann N., Bervanger T., Halmenschlager L. H., Busato S. B., et al. (2012). Memory-rescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders. Psychopharmacology 219 (4), 1133–1140. 10.1007/s00213-011-2449-3 PubMed DOI

Flores-Soto M. E., Chaparro-Huerta V., Escoto-Delgadillo M., Vazquez-Valls E., González-Castañeda R. E., Beas-Zarate C. (2012). Estructura y función de las subunidades del receptor a glutamato tipo NMDA [Structure and function of NMDA-type glutamate receptor subunits. Neurol. Barc. Spain) 27 (5), 301–310. 10.1016/j.nrl.2011.10.014 PubMed DOI

Frau R., Miczán V., Traccis F., Aroni S., Pongor C. I., Saba P., et al. (2019). Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone. Nat. Neurosci. 22 (12), 1975–1985. 10.1038/s41593-019-0512-2 PubMed DOI PMC

Fried P. A., Smith A. M. (2001). A literature review of the consequences of prenatal marihuana exposure. An emerging theme of a deficiency in aspects of executive function. Neurotoxicology Teratol. 23 (1), 1–11. 10.1016/s0892-0362(00)00119-7 PubMed DOI

Frieling H., Albrecht H., Jedtberg S., Gozner A., Lenz B., Wilhelm J., et al. (2009). Elevated cannabinoid 1 receptor mRNA is linked to eating disorder related behavior and attitudes in females with eating disorders. Psychoneuroendocrinology 34 (4), 620–624. 10.1016/j.psyneuen.2008.10.014 PubMed DOI

Fusar-Poli P., Crippa J. A., Bhattacharyya S., Borgwardt S. J., Allen P., Martin-Santos R., et al. (2009). Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Archives general psychiatry 66 (1), 95–105. 10.1001/archgenpsychiatry.2008.519 PubMed DOI

García-Baos A., Puig-Reyne X., García-Algar Ó., Valverde O. (2021). Cannabidiol attenuates cognitive deficits and neuroinflammation induced by early alcohol exposure in a mice model. Biomed. Pharmacother. = Biomedecine Pharmacother. 141, 111813. 10.1016/j.biopha.2021.111813 PubMed DOI

García-Gutiérrez M. S., Navarrete F., Gasparyan A., Austrich-Olivares A., Sala F., Manzanares J. (2020). Cannabidiol: A potential new alternative for the treatment of anxiety, depression, and psychotic disorders. Biomolecules 10 (11), 1575. 10.3390/biom10111575 PubMed DOI PMC

Gawel K., Gibula E., Marszalek-Grabska M., Filarowska J., Kotlinska J. H. (2019). Assessment of spatial learning and memory in the Barnes maze task in rodents-methodological consideration. Naunyn-Schmiedeberg's archives Pharmacol. 392 (1), 1–18. 10.1007/s00210-018-1589-y PubMed DOI PMC

Gibula-Tarlowska E., Wydra K., Kotlinska J. H. (2020). Deleterious effects of ethanol, Δ(9)-tetrahydrocannabinol (THC), and their combination on the spatial memory and cognitive flexibility in adolescent and adult male rats in the Barnes maze task. Pharmaceutics 12 (7), 654. 10.3390/pharmaceutics12070654 PubMed DOI PMC

Goldschmidt L., Day N. L., Richardson G. A. (2000). Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicology Teratol. 22 (3), 325–336. 10.1016/s0892-0362(00)00066-0 PubMed DOI

Goto A. (2022). Synaptic plasticity during systems memory consolidation. Neurosci. Res. 183, 1–6. 10.1016/j.neures.2022.05.008 PubMed DOI

Groff D., Bollampally P., Buono F., Knehans A., Spotts H., Bone C. (2023). Interventions addressing cannabis use during pregnancy: A systematic review. J. Addict. Med. 17 (1), 47–53. 10.1097/ADM.0000000000001027 PubMed DOI

Guagnini F., Valenti M., Mukenge S., Matias I., Bianchetti A., Di Palo S., et al. (2006). Neural contractions in colonic strips from patients with diverticular disease: Role of endocannabinoids and substance P. Gut 55 (7), 946–953. 10.1136/gut.2005.076372 PubMed DOI PMC

Guilloux J. P., Seney M., Edgar N., Sibille E. (2011). Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: Relevance to emotionality and sex. J. Neurosci. methods 197 (1), 21–31. 10.1016/j.jneumeth.2011.01.019 PubMed DOI PMC

Habayeb O. M., Taylor A. H., Bell S. C., Taylor D. J., Konje J. C. (2008). Expression of the endocannabinoid system in human first trimester placenta and its role in trophoblast proliferation. Endocrinology 149 (10), 5052–5060. 10.1210/en.2007-1799 PubMed DOI

Hameed M., Prasad S., Jain E., Dogrul B. N., Al-Oleimat A., Pokhrel B., et al. (2023). Medical cannabis for chronic nonmalignant pain management. Curr. pain headache Rep. 27 (4), 57–63. 10.1007/s11916-023-01101-w PubMed DOI PMC

Hirvonen J., Goodwin R. S., Li C. T., Terry G. E., Zoghbi S. S., Morse C., et al. (2012). Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol. psychiatry 17 (6), 642–649. 10.1038/mp.2011.82 PubMed DOI PMC

Hložek T., Uttl L., Kadeřábek L., Balíková M., Lhotková E., Horsley R. R., et al. (2017). Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 27 (12), 1223–1237. 10.1016/j.euroneuro.2017.10.037 PubMed DOI

Huizink A. C., Mulder E. J. (2006). Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring. Neurosci. Biobehav. Rev. 30 (1), 24–41. 10.1016/j.neubiorev.2005.04.005 PubMed DOI

Huizink A. C. (2014). Prenatal cannabis exposure and infant outcomes: Overview of studies. Prog. neuro-psychopharmacology Biol. psychiatry 52, 45–52. 10.1016/j.pnpbp.2013.09.014 PubMed DOI

Kaplan J. S., Wagner J. K., Reid K., McGuinness F., Arvila S., Brooks M., et al. (2021). Cannabidiol exposure during the mouse adolescent period is without harmful behavioral effects on locomotor activity, anxiety, and spatial memory. Front. Behav. Neurosci. 15, 711639. 10.3389/fnbeh.2021.711639 PubMed DOI PMC

Keith D., El-Husseini A. (2008). Excitation control: Balancing PSD-95 function at the synapse. Front. Mol. Neurosci. 1, 4. 10.3389/neuro.02.004.2008 PubMed DOI PMC

Laprairie R. B., Bagher A. M., Kelly M. E., Denovan-Wright E. M. (2015). Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br. J. Pharmacol. 172 (20), 4790–4805. 10.1111/bph.13250 PubMed DOI PMC

Levendosky A. A., Bogat G. A., Lonstein J., Muzik M., Nuttall A. K. (2021). Longitudinal prospective study examining the effects of the timing of prenatal stress on infant and child regulatory functioning: The Michigan prenatal stress study protocol. BMJ open 11 (9), e054964. 10.1136/bmjopen-2021-054964 PubMed DOI PMC

Lima-Silva T. B., Fabrício A. T., Silva L. D. S. V. E., de Oliveira G. M., da Silva W. T., Kissaki P. T., et al. (2012). Training of executive functions in healthy elderly: Results of a pilot study. Dementia neuropsychologia 6 (1), 35–41. 10.1590/S1980-57642012DN06010006 PubMed DOI PMC

Liu L., Wong T. P., Pozza M. F., Lingenhoehl K., Wang Y., Sheng M., et al. (2004). Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Sci. (New York, N.Y.) 304 (5673), 1021–1024. 10.1126/science.1096615 PubMed DOI

Maniaci G., Picone P., Dimarco T., Lipari A., Brancato A., Cannizzaro C., et al. (2015). Psychodiagnostic assessment of pathological gamblers: a focus on personality disorders, clinical syndromes and alexithymia. International Journal of Mental Health and Addiction 13 (6), 728–739. 10.1007/s11469-015-9550-5 DOI

Mao K., You C., Lei D., Zhang H. (2015). High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect. Int. J. Clin. Exp. Med. 8 (6), 8820–8827. eCollection 2015 PubMed PMC

Marco E. M., García-Gutiérrez M. S., Bermúdez-Silva F. J., Moreira F. A., Guimarães F., Manzanares J., et al. (2011). Endocannabinoid system and psychiatry: In search of a neurobiological basis for detrimental and potential therapeutic effects. Front. Behav. Neurosci. 5, 63. 10.3389/fnbeh.2011.00063 PubMed DOI PMC

Masataka N. (2019). Anxiolytic effects of repeated cannabidiol treatment in teenagers with social anxiety disorders. Front. Psychol. 10, 2466. 10.3389/fpsyg.2019.02466 PubMed DOI PMC

Meyer E., Bonato J. M., Mori M. A., Mattos B. A., Guimarães F. S., Milani H., et al. (2021). Cannabidiol confers neuroprotection in rats in a model of transient global cerebral ischemia: Impact of hippocampal synaptic neuroplasticity. Mol. Neurobiol. 58 (10), 5338–5355. 10.1007/s12035-021-02479-7 PubMed DOI

Meyer F. S. L., Gee D. G. (2018). The role of the endocannabinoid system and genetic Variation in adolescent brain development. Neuropsychopharmacol. official Publ. Am. Coll. Neuropsychopharmacol. 43 (1), 21–33. 10.1038/npp.2017.143 PubMed DOI PMC

Muller C., Lynch D. L., Hurst D. P., Reggio P. H. (2021). TRPV1 activation by anandamide via a unique lipid pathway. J. Chem. Inf. Model. 61 (12), 5742–5746. 10.1021/acs.jcim.1c00893 PubMed DOI

Murphy M., Mills S., Winstone J., Leishman E., Wager-Miller J., Bradshaw H., et al. (2017). Chronic adolescent d9-tetrahydrocannabinol treatment of male mice leads to long-term cognitive and behavioral dysfunction, which are prevented by concurrent cannabidiol treatment. Cannabis cannabinoid Res. 2 (1), 235–246. 10.1089/can.2017.0034 PubMed DOI PMC

Nguyen V. H., Harley K. G. (2022). Prenatal cannabis use and infant birth outcomes in the pregnancy risk assessment monitoring system. J. Pediatr. 240, 87–93. 10.1016/j.jpeds.2021.08.088 PubMed DOI

Niloy N., Hediyal T. A., Vichitra C., Sonali S., Chidambaram S. B., Gorantla V. R., et al. (2023). Effect of cannabis on memory consolidation, learning and retrieval and its current legal status in India: A review. Biomolecules 13 (1), 162. 10.3390/biom13010162 PubMed DOI PMC

Oberbarnscheidt T., Miller N. S. (2020). The impact of cannabidiol on psychiatric and medical conditions. J. Clin. Med. Res. 12 (7), 393–403. 10.14740/jocmr4159 PubMed DOI PMC

Osborne A. L., Solowij N., Weston-Green K. (2017). A systematic review of the effect of cannabidiol on cognitive function: Relevance to schizophrenia. Neurosci. Biobehav. Rev. 72, 310–324. 10.1016/j.neubiorev.2016.11.012 PubMed DOI

Patel P. K., Leathem L. D., Currin D. L., Karlsgodt K. H. (2021). Adolescent neurodevelopment and vulnerability to psychosis. Biol. psychiatry 89 (2), 184–193. 10.1016/j.biopsych.2020.06.028 PubMed DOI PMC

Paul S. E., Hatoum A. S., Fine J. D., Johnson E. C., Hansen I., Karcher N. R., et al. (2021). Associations between prenatal cannabis exposure and childhood outcomes: Results from the ABCD study. JAMA psychiatry 78 (1), 64–76. 10.1001/jamapsychiatry.2020.2902 PubMed DOI PMC

Peng H., Li H., Wei Y., Zhang R., Chang X., Meng L., et al. (2023). Effects of prenatal exposure to THC on hippocampal neural development in offspring. Toxicol. Lett. 374, 48–56. 10.1016/j.toxlet.2022.12.007 PubMed DOI

Peres F. F., Levin R., Suiama M. A., Diana M. C., Gouvêa D. A., Almeida V., et al. (2016). Cannabidiol prevents motor and cognitive impairments induced by reserpine in rats. Front. Pharmacol. 7, 343. 10.3389/fphar.2016.00343 PubMed DOI PMC

Plescia F., Sardo P., Rizzo V., Cacace S., Marino R. A., Brancato A., et al. (2014). Pregnenolone sulphate enhances spatial orientation and object discrimination in adult male rats: Evidence from a behavioural and electrophysiological study. Behav. brain Res. 258, 193–201. 10.1016/j.bbr.2013.10.026 PubMed DOI

Pope H. G., Jr, Yurgelun-Todd D. (1996). The residual cognitive effects of heavy marijuana use in college students. JAMA 275 (7), 521–527. 10.1001/jama.275.7.521 PubMed DOI

Popoviç M., Biessels G. J., Isaacson R. L., Gispen W. H. (2001). Learning and memory in streptozotocin-induced diabetic rats in a novel spatial/object discrimination task. Behav. brain Res. 122 (2), 201–207. 10.1016/s0166-4328(01)00186-3 PubMed DOI

Portugalov A., Zaidan H., Gaisler-Salomon I., Hillard C. J., Akirav I. (2022). FAAH inhibition restores early life stress-induced alterations in PFC microRNAs associated with depressive-like behavior in male and female rats. Int. J. Mol. Sci. 23 (24), 16101. 10.3390/ijms232416101 PubMed DOI PMC

Pretzsch C. M., Freyberg J., Voinescu B., Lythgoe D., Horder J., Mendez M. A., et al. (2019). Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder. Neuropsychopharmacology 44 (8), 1398–1405. 10.1038/s41386-019-0333-8 PubMed DOI PMC

Prud'homme M., Cata R., Jutras-Aswad D. (2015). Cannabidiol as an intervention for addictive behaviors: A systematic review of the evidence. Subst. abuse Res. Treat. 9, 33–38. 10.4137/SART.S25081 PubMed DOI PMC

Raucci U., Pietrafusa N., Paolino M. C., Di Nardo G., Villa M. P., Pavone P., et al. (2020). Cannabidiol treatment for refractory epilepsies in pediatrics. Front. Pharmacol. 11, 586110. 10.3389/fphar.2020.586110 PubMed DOI PMC

Realini N., Vigano' D., Guidali C., Zamberletti E., Rubino T., Parolaro D. (2011). Chronic URB597 treatment at adulthood reverted most depressive-like symptoms induced by adolescent exposure to THC in female rats. Neuropharmacology 60 (2-3), 235–243. 10.1016/j.neuropharm.2010.09.003 PubMed DOI

Robledo-Menendez A., Vella M., Grandes P., Soria-Gomez E. (2022). Cannabinoid control of hippocampal functions: The where matters. FEBS J. 289 (8), 2162–2175. 10.1111/febs.15907 PubMed DOI

Rodríguez-Muñoz M., Cortés-Montero E., Pozo-Rodrigálvarez A., Sánchez-Blázquez P., Garzón-Niño J. (2015). The ON:OFF switch, σ1r-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: Implications in neurological disorders. Oncotarget 6 (34), 35458–35477. 10.18632/oncotarget.6064 PubMed DOI PMC

Saez T. M., Aronne M. P., Caltana L., Brusco A. H. (2014). Prenatal exposure to the CB1 and CB2 cannabinoid receptor agonist WIN 55,212-2 alters migration of early-born glutamatergic neurons and GABAergic interneurons in the rat cerebral cortex. J. Neurochem. 129 (4), 637–648. 10.1111/jnc.12636 PubMed DOI

Sánchez-Blázquez P., Rodríguez-Muñoz M., Garzón J. (2014). The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: Implications in psychosis and schizophrenia. Front. Pharmacol. 4, 169. 10.3389/fphar.2013.00169 PubMed DOI PMC

Schiavon A. P., Soares L. M., Bonato J. M., Milani H., Guimarães F. S., Weffort de Oliveira R. M. (2014). Protective effects of cannabidiol against hippocampal cell death and cognitive impairment induced by bilateral common carotid artery occlusion in mice. Neurotox. Res. 26 (4), 307–316. 10.1007/s12640-014-9457-0 PubMed DOI

Selvam R., Yeh M. L., Levine E. S. (2018). Endogenous cannabinoids mediate the effect of BDNF at CA1 inhibitory synapses in the hippocampus. Synapse 73, e22075. 10.1002/syn.22075 PubMed DOI PMC

Shannon S., Lewis N., Lee H., Hughes S. (2019). Cannabidiol in anxiety and sleep: A large case series. Perm. J. 23, 18–041. 10.7812/TPP/18-041 PubMed DOI PMC

Shiraishi-Yamaguchi Y., Furuichi T. (2007). The Homer family proteins. Genome Biol. 8 (2), 206. 10.1186/gb-2007-8-2-206 PubMed DOI PMC

Sholler D. J., Schoene L., Spindle T. R. (2020). Therapeutic efficacy of cannabidiol (CBD): A review of the evidence from clinical trials and human laboratory studies. Curr. Addict. Rep. 7 (3), 405–412. 10.1007/s40429-020-00326-8 PubMed DOI PMC

Skully J. (2021). Oral cbd administration: Assessing bioavailability and behavioral outcomes in A rodent model. Detroit: Wayne State University Theses. https://digitalcommons.wayne.edu/oa_theses/834.

Solowij N., Broyd S. J., Beale C., Prick J. A., Greenwood L. M., van Hell H., et al. (2018). Therapeutic effects of prolonged cannabidiol treatment on psychological symptoms and cognitive function in regular cannabis users: A pragmatic open-label clinical trial. Cannabis cannabinoid Res. 3 (1), 21–34. 10.1089/can.2017.0043 PubMed DOI PMC

Spear L. P. (2013). Adolescent neurodevelopment. J. Adolesc. health 52, S7–S13. 10.1016/j.jadohealth.2012.05.006 PubMed DOI PMC

Straiker A., Dvorakova M., Zimmowitch A., Mackie K. (2018). Cannabidiol inhibits endocannabinoid signaling in autaptic hippocampal neurons. Mol. Pharmacol. 94 (1), 743–748. 10.1124/mol.118.111864 PubMed DOI PMC

Sweatt J. D. (2010). Rodent behavioral learning and memory models in mechanisms of memory. Cambridge: Academic Press. 76–103.

Sylantyev S., Jensen T. P., Ross R. A., Rusakov D. A. (2013). Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc. Natl. Acad. Sci. U. S. A. 110 (13), 5193–5198. 10.1073/pnas.1211204110 PubMed DOI PMC

Taneja S., Panday J., Popoola A., Greyson D., McDonald S. D., Patel T., et al. (2022). Making informed choices about cannabis use during pregnancy and lactation: A qualitative study of information use. Birth (Berkeley, Calif). 10.1111/birt.12668 PubMed DOI

Thomason M. E., Palopoli A. C., Jariwala N. N., Werchan D. M., Chen A., Adhikari S., et al. (2021). Miswiring the brain: Human prenatal Δ9-tetrahydrocannabinol use associated with altered fetal hippocampal brain network connectivity. Dev. Cogn. Neurosci. 51, 101000. 10.1016/j.dcn.2021.101000 PubMed DOI PMC

Tortoriello G., Morris C. V., Alpar A., Fuzik J., Shirran S. L., Calvigioni D., et al. (2014). Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J. 33 (7), 668–685. 10.1002/embj.201386035 PubMed DOI PMC

Twardowschy A., Castiblanco-Urbina M. A., Uribe-Mariño A., Biagioni A. F., Salgado-Rohner C. J., Crippa J. A., et al. (2013). The role of 5-HT1A receptors in the anti-aversive effects of cannabidiol on panic attack-like behaviors evoked in the presence of the wild snake Epicrates cenchria crassus (Reptilia, Boidae). J. Psychopharmacol. Oxf. Engl. 27 (12), 1149–1159. 10.1177/0269881113493363 PubMed DOI

Tymofiyeva O., Gaschler R. (2021). Training-induced neural plasticity in youth: A systematic review of structural and functional mri studies. Front. Hum. Neurosci. 14, 497245. 10.3389/fnhum.2020.497245 PubMed DOI PMC

Umpierrez L. S., Costa P. A., Michelutti E. A., Baracz S. J., Sauer M., Turner A. J., et al. (2022). Cannabidiol but not cannabidiolic acid reduces behavioural sensitisation to methamphetamine in rats, at pharmacologically effective doses. Psychopharmacology 239 (5), 1593–1603. 10.1007/s00213-022-06119-3 PubMed DOI PMC

Vargish G. A., Pelkey K. A., Yuan X., Chittajallu R., Collins D., Fang C., et al. (2017). Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure. Mol. psychiatry 22 (1), 56–67. 10.1038/mp.2016.17 PubMed DOI PMC

Wang X., Dow-Edwards D., Keller E., Hurd Y. L. (2003). Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain. Neuroscience 118 (3), 681–694. 10.1016/s0306-4522(03)00020-4 PubMed DOI

Wei D., Piomelli D. (2015). Cannabinoid-based drugs: Potential applications in addiction and other mental disorders. FOCUS 13 (3), 307–316. 10.1176/appi.focus.20150009 DOI

Weston-Green K. (2019). The united chemicals of cannabis: Beneficial effects of cannabis phytochemicals on the brain and cognition. IntechOpen. 10.5772/intechopen.79266 DOI

Wilson W. H., Ellinwood E. H., Mathew R. J., Johnson K. (1994). Effects of marijuana on performance of a computerized cognitive-neuromotor test battery. Psychiatry Res. 51 (2), 115–125. 10.1016/0165-1781(94)90031-0 PubMed DOI

Winters B. L., Vaughan C. W. (2021). Mechanisms of endocannabinoid control of synaptic plasticity. Neuropharmacology 197, 108736. 10.1016/j.neuropharm.2021.108736 PubMed DOI

Wise L. E., Thorpe A. J., Lichtman A. H. (2009)., 34. Neuropsychopharmacology, 2072–2080. 10.1038/npp.2009.31 Hippocampal CB(1) receptors mediate the memory impairing effects of Delta(9)-tetrahydrocannabinol official Publ. Am. Coll. Neuropsychopharmacol. 9 PubMed DOI PMC

Wu C. S., Jew C. P., Lu H. C. (2011). Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain. Future neurol. 6 (4), 459–480. 10.2217/fnl.11.27 PubMed DOI PMC

Xu J. Y., Chen C. (2015). Endocannabinoids in synaptic plasticity and neuroprotection. Neurosci. a Rev. J. bringing Neurobiol. neurology psychiatry 21 (2), 152–168. 10.1177/1073858414524632 PubMed DOI PMC