Skip to main content

Advertisement

SpringerLink
Log in

Cannabidiol for the treatment of autism spectrum disorder: hope or hype?

  • Review
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Autism spectrum disorder (ASD) is defined as a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction, restricted and repetitive patterns of behavior, and varying levels of intellectual disability. ASD is observed in early childhood and is one of the most severe chronic childhood disorders in prevalence, morbidity, and impact on society. It is usually accompanied by attention deficit hyperactivity disorder, anxiety, depression, sleep disorders, and epilepsy. The treatment of ASD has low efficacy, possibly because it has a heterogeneous nature, and its neurobiological basis is not clearly understood. Drugs such as risperidone and aripiprazole are the only two drugs available that are recognized by the Food and Drug Administration, primarily for treating the behavioral symptoms of this disorder. These drugs have limited efficacy and a high potential for inducing undesirable effects, compromising treatment adherence. Therefore, there is great interest in exploring the endocannabinoid system, which modulates the activity of other neurotransmitters, has actions in social behavior and seems to be altered in patients with ASD. Thus, cannabidiol (CBD) emerges as a possible strategy for treating ASD symptoms since it has relevant pharmacological actions on the endocannabinoid system and shows promising results in studies related to disorders in the central nervous system.

Objectives

Review the preclinical and clinical data supporting CBD’s potential as a treatment for the symptoms and comorbidities associated with ASD, as well as discuss and provide information with the purpose of not trivializing the use of this drug.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abdul-Monim Z, Neill JC, Reynolds GP (2007) Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat. J Psychopharmacol 21:198–205

    Article  CAS  PubMed  Google Scholar 

  • Adams R, Hunt M, Clark JH (1940) Structure of cannabidiol, a product isolated from the Marihuana extract of Minnesota Wild Hemp I. J Am Chem Soc 62:196–200

  • Ajram LA, Horder J, Mendez MA, Galanopoulos A, Brennan LP, Wichers RH et al (2017) Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder Transl. Psychiatry 7:e1137

    CAS  Google Scholar 

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (5th ed.) American Psychiatric Association press, Washington, DC

  • Anagnostou E, Soorya L, Chaplin W, Bartz J, Halpern D, Wasserman S et al (2012) Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 3:1–9

    Article  CAS  Google Scholar 

  • Aran A, Cassuto H, Lubotzky A, Wattad N, Hazan E (2019) Brief report: cannabidiol-rich cannabis in children with autism spectrum disorder and severe behavioral problems—a retrospective feasibility study. J Autism Dev Disord 49:1284–1288

    Article  PubMed  Google Scholar 

  • Aran A, Eylon M, Harel M, Polianski L, Nemirovski A, Tepper S et al (2019) Lower circulating endocannabinoid levels in children with autism spectrum disorder. Mol Autism 10:1–11

    Article  Google Scholar 

  • Aran A, Harel M, Cassuto H, Polyansky L, Schnapp A, Wattad N, Shmueli D, Golan D, Castellanos FX (2021) Cannabinoid treatment for autism: a proof-of-concept randomized trial. Mol Autism 12:1–11

    Article  CAS  Google Scholar 

  • Araujo DJ, Tjoa K, Saijo K (2019) The endocannabinoid system as a window into microglial biology and its relationship to autism. Front Cell Neurosci 13:1–7

    Article  CAS  Google Scholar 

  • Ashwood P, Wills S, Van de Water J (2006) The immune response in autism: a new frontier for autism research. J Leukoc Biol 80:1–15

    Article  CAS  PubMed  Google Scholar 

  • Atladóttir HÓ, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdalla M et al (2010) Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord 40:1423–1430

    Article  PubMed  Google Scholar 

  • Bagot KS, Mili R, Kaminer Y (2015) Adolescent initiation of cannabis use and early-onset psychosis. Subst Abus 36:524–533

    Article  PubMed  Google Scholar 

  • Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, Warren Z et al (2018) Prevalence of autism spectrum disorder among children aged 8 Years - Autism and developmental disabilities monitoring network, 11 Sites, United States, 2014 MMWR. Surveill Summ 67:1–23

    Article  Google Scholar 

  • Balachandran P, Elsohly M, Hill KP (2021) Cannabidiol interactions with medications, illicit substances, and alcohol: a comprehensive review. J Gen Intern Med 36:2074–2084

    Article  PubMed  PubMed Central  Google Scholar 

  • Baranova J, Dragunas G, Botellho MCS, Ayub ALP, Bueno-Alves R, Alencar RR, Papaiz DD, Sogayar MC, Ulrich H, Correa RG (2021) Autism spectrum disorder: signaling pathways and prospective therapeutic targets. Cell Mol Neurobiol 41:619–649

    Article  PubMed  Google Scholar 

  • Barchel D, Stolar O, De-Haan T, Ziv-Baran T, Saban N, Fuchs DO, Koren G, Berkovitch M (2019) Oral cannabidiol use in children with autism spectrum disorder to treat related symptoms and co-morbidities. Front Pharmacol 9:1521

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bargiela S, Steward R, Mandy W (2016) The experiences of late-diagnosed women with autism spectrum conditions: an investigation of the female autism phenotype. J Autism Dev Disord 46:3281–3294

    Article  PubMed  PubMed Central  Google Scholar 

  • Batalla A, Bos J, Postma A, Bossong MG (2021) The impact of cannabidiol on human brain function: a systematic review. Front in Pharmacol 11:618184

    Article  CAS  Google Scholar 

  • Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:1094–1097

    Article  CAS  PubMed  Google Scholar 

  • Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R, Hallak JE, Zuardi AW, Crippa JA (2011) Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology 36:1219–1226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernaerts S, Boets B, Bosmans G, Steyaert J, Alaerts K (2020) Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up. Mol Autism 11:1–14

    Article  CAS  Google Scholar 

  • Besag FMC (2018) Epilepsy in patients with autism: links, risks and treatment challenges. Neuropsychiatr Dis Treat 14:1–10

    Article  PubMed  Google Scholar 

  • Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martin-Santos R, Nosarti C, O’Carroll C, Allen P, Seal ML, Fletcher PC, Crippa JA, Giampietro V, Mechelli A, Atakan Z, McGuire P (2009) Modulation of mediotemporal and ventrostriatal function in humans by delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis. Arch Gen Psychiatry 66:442–451

    Article  CAS  PubMed  Google Scholar 

  • Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T et al (2010) Opposite effects of δ-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35:764–774

    Article  CAS  PubMed  Google Scholar 

  • 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 3:53

    Article  PubMed  PubMed Central  Google Scholar 

  • Bisogno T, Hanuš L, De Petrocellis L, Tchilibon S, Ponde DE, 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 134:845–852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bogaty SER, Lee RSC, Hickie IB, Hermens DF (2018) Meta-analysis of neurocognition in young psychosis patients with current cannabis use. J Psychiatr Res 99:22–32

    Article  PubMed  Google Scholar 

  • Bölte S, Girdler S, Marschik PB (2019) The contribution of environmental exposure to the etiology of autism spectrum disorder. Cell Mol Life Sci 76:1275–1297

    Article  PubMed  CAS  Google Scholar 

  • Breivogel CS, Sim LJ, Childers SR (1997) Regional differences in cannabinoid receptor/G-protein coupling in rat brain. J Pharmacol Exp Ther 282:1632–1642

    CAS  PubMed  Google Scholar 

  • Brown JD, Winterstein AG (2019) Potential adverse drug events and drug–drug interactions with medical and consumer Cannabidiol (CBD) use. J Clin Med 8:989

    Article  CAS  PubMed Central  Google Scholar 

  • Brugha TS, McManus S, Bankart J, Scott F, Purdon S, Smith J et al (2011) Epidemiology of autism spectrum disorders in adults in the community in England. Arch Gen Psychiatry 68:459–465

    Article  PubMed  Google Scholar 

  • Bugalho P, Correa B, Viana-Baptista M (2006) Role of the cerebellum in cognitive and behavioral control: scientific basis and investigation models. Acta Med Port 19:257–267

    PubMed  Google Scholar 

  • Campos AC, Guimarães FS (2008) Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology 199:223–230

    Article  CAS  PubMed  Google Scholar 

  • Campos AC, Ortega Z, Palazuelos J, Fogaça MV, Aguiar DC, Díaz-Alonso J, Ortega-Gutiérrez S, Vázquez-Villa H, Moreira FA, Guzmán M, Galve-Roperh I, Guimarães FS (2013) The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol 16:1407–1419

    Article  CAS  PubMed  Google Scholar 

  • Capano L, Dupuis A, Brian J, Mankad D, Genore L, Adams RH, Smile S (2018) A pilot dose finding study of pioglitazone in autistic children. Mol Autism 9:59. https://pubmed.ncbi.nlm.nih.gov/30498564/

  • Carbone E, Manduca A, Cacchione C, Vicari S, Trezza V (2021) Healing autism spectrum disorder with cannabinoids: a neuroinflammatory story. Neurosci Biobehav Rev 121:128–143

    Article  CAS  PubMed  Google Scholar 

  • Careaga M, Murai T, Bauman MD (2017) Maternal immune activation and autism spectrum disorder: from rodents to nonhuman and human primates. Biol Psychiatry 81:391–401

    Article  CAS  PubMed  Google Scholar 

  • Carlini EA (2010) The research on marijuana in Brazil. Braz J Psychiatry 32:53–54

    Article  Google Scholar 

  • Carlini EA, Mechoulam R, Lander N (1975) Anticonvulsant activity of four oxygenated cannabidiol derivatives. Res Commun Chem Pathol Pharmacol 12:1–15

    CAS  PubMed  Google Scholar 

  • Carrier EJ, Auchampach JA, Hillard CJ (2006) Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci 103:7895–7900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carter CS (2014) Oxytocin pathways and the evolution of human behavior. Annu Rev Psychol 65:17–39

    Article  PubMed  Google Scholar 

  • Casarotto PC, Resstel Gomes FV, LBM, Guimarães, F S, (2010) Cannabidiol inhibitory effect on marble-burying behavior: involvement of CB1 receptors. Behav Pharmacol 21:353–358

    Article  CAS  PubMed  Google Scholar 

  • Chadwick B, Miller ML, Hurd YL (2013) Cannabis use during adolescent development: susceptibility to psychiatric illness. Front Psychiatry 4:1–8

    Article  Google Scholar 

  • Chakrabarti B, Baron-Cohen S (2011) Variation in the human cannabinoid receptor CNR1 gene modulates gaze duration for happy faces. Mol Autism 2:1–7

    Article  CAS  Google Scholar 

  • Chakrabarti B, Kent L, Suckling J, Bullmore E, Baron-Cohen S (2006) Variations in the human cannabinoid receptor (CNR1) gene modulate striatal responses to happy faces. Eur J Neurosci 23:1944–1948

    Article  PubMed  Google Scholar 

  • Chevallier C, Kohls G, Troiani V, Brodkin ES, Schultz RT (2012) The social motivation theory of autism. Trends Cogn Sci 16:231–239

    Article  PubMed  PubMed Central  Google Scholar 

  • Choi GB, Won H, Yim YS, Kim SV, Cai Y, Hoeffer CA et al (2016) The maternal ROR γ t / IL-17a pathway promotes autism-like phenotypes in offspring. Science 351:933–940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clayton N, Marshall FH, Bountra C, O’Shaughnessy CT (2002) CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain 96:253–260

    Article  CAS  PubMed  Google Scholar 

  • Cochran DM, Sikoglu EM, Hodge SM, Edden RAE, Foley A, Kennedy DN et al (2015) Relationship among glutamine, γ-aminobutyric acid, and social cognition in autism spectrum disorders. J Child Adolesc Psychopharmacol 25:314–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coghlan S, Horder J, Inkster B, Mendez MA, Murphy DG, Nutt DJ (2012) GABA system dysfunction in autism and related disorders: from synapse to symptoms. Neurosci Biobehav Rev 36:2044–2055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Consroe P, Carlini EA, Zwicker AP, Lacerda LA (1979) Interaction of cannabidiol and alcohol in humans. Psychopharmacology 66:45–50

    Article  CAS  PubMed  Google Scholar 

  • Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 7:83–87

    Article  Google Scholar 

  • Crippa JAS, Nogueira Derenusson G, Borduqui Ferrari T, Wichert-Ana L, Duran FLS, Martin-Santos R et al (2011) Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol 25:121–130

    Article  CAS  PubMed  Google Scholar 

  • Crippa JA, Guimarães FS, Campos AC, Zuardi AW (2018) Translational investigation of the therapeutic potential of cannabidiol (CBD): toward a new age. Front Immunol 9:2009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cristino L, Bisogno T, Di Marzo V (2020) Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol 16:9–29

    Article  PubMed  Google Scholar 

  • Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R et al (1980) Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21:175–185

    Article  CAS  PubMed  Google Scholar 

  • Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J et al (2003) Maternal neuronal antibodies associated with autism and a language disorder. Ann Neurol 53:533–537

    Article  PubMed  Google Scholar 

  • Damkier P, Lassen D, Christensen MMH, Madsen KG, Hellfritzsch M, Pottegård A (2019) Interaction between warfarin and cannabis. Basic Clin Pharmacol Toxicol 124:28–31

    Article  CAS  PubMed  Google Scholar 

  • De Souza Crippa JA, Zuardi AW, Garrido GEJ, Wichert-Ana L, Guarnieri R, Ferrari L et al (2004) Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology 29:417–426

    Article  CAS  Google Scholar 

  • Devane WA (1994) New dawn of cannabinoid pharmacology. Trends Pharmacol Sci 15:40–41

    Article  CAS  PubMed  Google Scholar 

  • Devane WA, Hanuš L, Breuer A, Pertwee RG, Stevenson LA et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    Article  CAS  PubMed  Google Scholar 

  • Di Marzo V (2020) The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders. Dialogues Clin Neurosci 22:259–269

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Marzo V, Maccarrone M (2008) FAAH and anandamide: is 2-AG really the odd one out? Trends Pharmacol Sci 29:229–233

    Article  PubMed  CAS  Google Scholar 

  • Dinh TP, Freund TF, Piomelli D (2002) A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. Chem Phys Lipids 121:149–158

    Article  CAS  PubMed  Google Scholar 

  • Doenni VM, Gray JM, Song CM, Patel S, Hill MN, Pittman QJ (2016) Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling. Brain Behav Immun 58:237–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Domschke K, Dannlowski U, Ohrmann P, Lawford B, Bauer J, Kugel H et al (2008) Cannabinoid receptor 1 (CNR1) gene: impact on antidepressant treatment response and emotion processing in Major Depression. Eur Neuropsychopharmacol 18:751–759

    Article  CAS  PubMed  Google Scholar 

  • Dos-Santos-Pereira M, Guimarães FS, Del-Bel E, Raisman-Vozari R, Michel PP (2020) Cannabidiol prevents LPS-induced microglial inflammation by inhibiting ROS/NF-κB-dependent signaling and glucose consumption. Glia 68:561–573

    Article  PubMed  Google Scholar 

  • Egertová M, Giang DK, Cravatt BF, Elphick MR (1998) A new perspective on cannabinoid signaling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proc R Soc B Biol Sci 265:2081–2085

    Article  Google Scholar 

  • Elmes SJR, Jhaveri MD, Smart D, Kendall DA, Chapman V (2004) Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naïve rats and in rat models of inflammatory and neuropathic pain. Eur J Neurosci 20:2311–2320

    Article  PubMed  Google Scholar 

  • Englund A, Morrison PD, Nottage J, Hague D, Kane F, Bonaccorso S et al (2013) Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol 27:19–27

    Article  CAS  PubMed  Google Scholar 

  • Enstrom AM, Onore CE, Van de Water JA, Ashwood P (2010) Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav Immun 24:64–71

    Article  CAS  PubMed  Google Scholar 

  • Erlander MG, Tobin AJ (1991) The structural and functional heterogeneity of glutamic acid decarboxylase: A review. Neurochem Res 16:215–226

    Article  CAS  PubMed  Google Scholar 

  • Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR (2002) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry 52:805–810

    Article  CAS  PubMed  Google Scholar 

  • Fattore L, Fratta W (2010) How important are sex differences in cannabinoid action? Br J Pharmacol 160:544–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fleury-Teixeira P, Caixeta FV, da Silva LCR, Brasil-Neto JP, Malcher-Lopes R (2019) Effects of cbd-enriched cannabis sativa extract on autism spectrum disorder symptoms: an observational study of 18 participants undergoing compassionate use. Front Neurol 10:1–9

    Article  Google Scholar 

  • Fogaça MV, Campos AC, Coelho LD, Duman RS, Guimarães FS (2018) The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology 135:22–33

    Article  PubMed  CAS  Google Scholar 

  • Folkes MO, Báldi R, Kondev V, Marcus DJ, Hartley ND, Turner BD, Ayers JK, Baechle JJ, Misra MP, Altemus M, Grueter CA, Grueter BA, Patel S (2020) An endocannabinoid-regulated basolateral amygdala–nucleus accumbens circuit modulates sociability. J Clin Invest 130:1728–1742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franco V, Perucca E (2019) Pharmacological and therapeutic properties of cannabidiol for epilepsy. Drugs 79:1435–1454

    Article  CAS  PubMed  Google Scholar 

  • Fride E, Gobshtis N, Dahan H, Weller A, Giuffrida A, Ben-Shabat S (2009) Chapter 6 the endocannabinoid system during development: emphasis on perinatal events and delayed effects. Vitam Horm 81:139–158

    Article  CAS  PubMed  Google Scholar 

  • Gaston TE, Szaflarski JP (2018) Cannabis for the treatment of epilepsy: an update. Curr Neurol Neurosci Rep 18:73

    Article  PubMed  CAS  Google Scholar 

  • Giraud C, Tran A, Rey E, Vincent J, Tréluyer J-M, Pons G (2004) In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19. Drug Metab Dispos 32:1279–1286

    Article  CAS  PubMed  Google Scholar 

  • Gogolla N, LeBlanc JJ, Quast KB, Südhof TC, Fagiolini M, Hensch TK (2009) Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord 1:172–181

    Article  PubMed  PubMed Central  Google Scholar 

  • Gomes FV, Issy AC, Ferreira FR, Viveros MP, Del Bel EA, Guimarães FS (2015) Cannabidiol attenuates sensorimotor gating disruption and molecular changes induced by chronic antagonism of NMDA receptors in Mice. Int J Neuropsychopharmacol 18:1–10

    Article  Google Scholar 

  • Gomes FV, Llorente R, Del Bel EA, Viveros MP, López-Gallardo M, Guimarães FS (2015) Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr Res 164:155–163

    Article  PubMed  Google Scholar 

  • Guimarães FS, Chiaretti TM, Graeff FG, Zuardi AW (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology 100:558–559

    Article  PubMed  Google Scholar 

  • Gururajan A, Taylor DA, Malone DT (2011) Effect of cannabidiol in a MK-801-rodent model ofaspects of schizophrenia. Behav Brain Res 222:299–308

    Article  CAS  PubMed  Google Scholar 

  • Harkany T, Keimpema E, Barabás K, Mulder J (2008) Endocannabinoid functions controlling neuronal specification during brain development. Mol Cell Endocrinol 286:84–90

    Article  CAS  Google Scholar 

  • Hartmann A, Lisboa SF, Sonego AB, Coutinho D, Gomes FV, Guimarães FS (2019) Cannabidiol attenuates aggressive behavior induced by social isolation in mice: involvement of 5-HT1A and CB1 receptors. Prog Neuro-Psychopharmacology Biol Psychiatry 94:109637

    Article  CAS  Google Scholar 

  • Herbert MR (2010) Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol 23:103–110

    Article  PubMed  Google Scholar 

  • Ho KW, Ward NJ, Calkins DJ (2012) TRPV1: a stress response protein in the central nervous system. Am J Neurodegener Dis 1:1–14

    PubMed  PubMed Central  Google Scholar 

  • Horder J, Wilson CE, Mendez MA, Murphy DG (2014) Autistic traits and abnormal sensory experiences in adults. J Autism Dev Disord 44:1461–1469

    Article  PubMed  Google Scholar 

  • Howlett AC, Blume LC, Dalton DG (2010) CB 1 Cannabinoid receptors and their associated proteins. Curr Med Chem 17:1382–1393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hudson R, Rushlow W, Laviolette RS (2018) Phytocannabinoids modulate emotional memory processing through interactions with the ventral hippocampus and mesolimbic dopamine system: implications for neuropsychiatric pathology. Psychopharmacology 235:447–458

    Article  CAS  PubMed  Google Scholar 

  • Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET et al (2001) Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 58:322–328

    Article  CAS  PubMed  Google Scholar 

  • Hunt GE, Large MM, Cleary M, Lai HMX, Saunders JB (2018) Prevalence of comorbid substance use in schizophrenia spectrum disorders in community and clinical settings, 1990–2017: systematic review and meta-analysis. Drug Alcohol Depend 191:234–258

    Article  PubMed  Google Scholar 

  • Iversen L (1994) Endogenous cannabinoids. Nature 372:619–619

    Article  CAS  PubMed  Google Scholar 

  • Jackson AR, Nagarkatti P, Nagarkatti M (2014) Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction. PLoS ONE 9:e93954

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X (2005) Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Invest 115:3104–3116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K (2011) Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci 89:165–170

    Article  CAS  PubMed  Google Scholar 

  • Jiang R, Yamaori S, Okamoto Y, Yamamoto I, Watanabe K (2013) Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet 28:332–338

    Article  CAS  PubMed  Google Scholar 

  • Jiang HY, Xu LL, Shao L, Xia RM, Yu ZH, Ling ZX et al (2016) Maternal infection during pregnancy and risk of autism spectrum disorders: a systematic review and meta-analysis. Brain Behav Immun 58:165–172

    Article  PubMed  Google Scholar 

  • Kaminski NE, Abood ME, Kessler FK, Martin BR, Schatz AR (1992) Identification of a functionally relevant cannabinoid receptor on mouse spleen cells that is involved in cannabinoid-mediated immune modulation. Mol Pharmacol 42:736–742

    CAS  PubMed  Google Scholar 

  • Kaplan JS, Stella N, Catterall WA, Westenbroek RE (2017) Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc of the Natl Acad of Sci 114:11229–11234

    Article  CAS  Google Scholar 

  • Karhson DS, Krasinska KM, Dallaire JA, Libove RA, Phillips JM, Chien AS et al (2018) Plasma anandamide concentrations are lower in children with autism spectrum disorder. Mol Autism 9:1–6

    Article  CAS  Google Scholar 

  • Kirsten TB, Taricano M, Maiorka PC, Palermo-Neto J, Bernardi MM (2010) Prenatal lipopolysaccharide reduces social behavior in male offspring. NeuroImmunoModulation 17:240–251

    Article  CAS  PubMed  Google Scholar 

  • Kiyono T, Morita M, Morishima R, Fujikawa S, Yamasaki S, Nishida A, Ando S, Kasai K (2020) The prevalence of psychotic experiences in autism spectrum disorder and autistic traits: a systematic review and meta-analysis. Schizophrenia Bulletin Open 1

  • Knuesel I, Chicha L, Britschgi M, Schobel SA, Bodmer M, Hellings JA et al (2014) Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol 10:643–660

    Article  CAS  PubMed  Google Scholar 

  • Koskinen J, Löhönen J, Koponen H, Isohanni M, Miettunen J (2010) Rate of cannabis use disorders in clinical samples of patients with schizophrenia: a meta-analysis. Schizophr Bull 36:1115–11130

    Article  PubMed  Google Scholar 

  • Kozela E, Juknat A, Vogel Z (2017) Modulation of astrocyte activity by cannabidiol, a nonpsychoactive cannabinoid. Int J Mol Sci 18:1669

  • Kuester G, Vergara K, Ahumada A, Gazmuri AM (2017) Oral cannabis extracts as a promising treatment for the core symptoms of autism spectrum disorder: preliminary experience in Chilean patients. J Neurol Sci 381:932–933

    Article  Google Scholar 

  • Laezza C, Pagano C, Navarra G, Pastorino O, Proto MC, Fiore D et al (2020) The endocannabinoid system: a target for cancer treatment. Int J Mol Sci 21:747

    Article  CAS  PubMed Central  Google Scholar 

  • Lai MC, Baron-Cohen S (2015) Identifying the lost generation of adults with autism spectrum conditions. Lancet Psychiatry 2:1013–1027

    Article  PubMed  Google Scholar 

  • Lai M, Lombardo M, Baron-Cohen S (2014) Autism. Autism. Lancet 383:896–910

    Article  PubMed  Google Scholar 

  • Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 172:4790–4805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Large M, Sharma S, Compton MT, Slade T, Nielssen O (2011) Cannabis use and earlier onset of psychosis: a systematic meta-analysis. Arch Gen Psychiatry 68:555–651

    Article  PubMed  Google Scholar 

  • Lee JLC, Bertoglio LJ, Guimarães FS, Stevenson CW (2017) Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. Br J Pharmacol 174:3242–3256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lenz KM, Nelson LH (2018) Microglia and beyond: Innate immune cells as regulators of brain development and behavioral function. Front Immunol 9:698

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Levy D, Ronemus M, Yamrom B, Lee Y, Leotta A, Kendall J et al (2011) Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70:886–897

    Article  CAS  PubMed  Google Scholar 

  • Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M, Koethe D (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2:e94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Libbey JE, Sweeten TL, McMahon WM, Fujinami RS (2005) Autistic disorder and viral infections. J Neurovirol 11:1–10

    Article  PubMed  Google Scholar 

  • Linge R, Jiménez-Sánchez L, Campa L, Pilar-Cuéllar F, Vidal R, Pazos A et al (2016) Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology 103:16–26

    Article  CAS  PubMed  Google Scholar 

  • Litvin Y, Phan A, Hill MN, Pfaff DW, McEwen BS (2013) CB1 receptor signaling regulates social anxiety and memory. Genes Brain Behav 12:479–489

    Article  CAS  PubMed  Google Scholar 

  • Lu J, Fan S, Zou G et al (2018) Involvement of glycine receptor a1 subunits in cannabinoid-induced analgesia. Neuropharmacology 133:224–232

    Article  CAS  PubMed  Google Scholar 

  • Luna B, Marek S, Larsen B, Tervo-Clemmens B, Chahal R (2015) An integrative model of the maturation of cognitive control. Annu Rev Neurosci 38:151–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lyall K, Ashwood P, Van de Water J, Hertz-Picciotto I (2014) Maternal immune-mediated conditions, autism spectrum disorders, and developmental delay. J Autism Dev Disord 44:1546–1555

    PubMed  PubMed Central  Google Scholar 

  • Maccarrone M, Guzman M, Mackie K, Doherty P, Harkany T (2014) Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci 15:786–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manduca A, Carbone E, Schiavi S, Cacchione C, Buzzelli V, Campolongo P, Trezza V (2021) The neurochemistry of social reward during development: what have we learned from rodent models? J Neurochem 157:1408–1435

    Article  CAS  PubMed  Google Scholar 

  • Marconi A, Di Forti M, Lewis CM, Murray RM, Vassos E (2016) Meta-analysis of the association between the level of cannabis use and risk of psychosis. Schizophr Bull 42:1262–1269

    Article  PubMed  PubMed Central  Google Scholar 

  • Martin BR, Compton DR, Thomas BF, Prescott WR, Little PJ, Razdan RK, Johnson MR, Melvin LS, Mechoulam R, Susan JW (1991) Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacol Biochem Behav 40:471–478

    Article  CAS  PubMed  Google Scholar 

  • Martin-Santos R, Crippa JA, Batalla A, Bhattacharyya S, Atakan Z, Borgwardt S, Allen P, Seal M, Langohr K, Farré M, Zuardi AW, McGuire PK (2012) Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des 18:4966–4979

    Article  CAS  PubMed  Google Scholar 

  • Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564

    Article  CAS  PubMed  Google Scholar 

  • Matta SM, Hill-Yardin EL, Crack PJ (2019) The influence of neuroinflammation in Autism Spectrum Disorder. Brain Behav Immun 79:75–90

    Article  PubMed  Google Scholar 

  • McFadden K, Minshew NJ (2013) Evidence for dysregulation of axonal growth and guidance in the etiology of ASD. Front Hum Neurosci 7:671

    Article  PubMed  PubMed Central  Google Scholar 

  • Mechoulam R, Shvo Y (1963) Hashish-I the structure of cannabidiol. Tetrahedron 19:2073–2078

    Article  CAS  PubMed  Google Scholar 

  • Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90

    Article  CAS  PubMed  Google Scholar 

  • Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, McDonald K, Ward A, Poulton R, Moffitt TE (2012) Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci 109:E2657–E2664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melancia F, Schiavi S, Servadio M, Cartocci V, Campolongo P, Palmery M, Pallottini V, Trezza V (2018) Sex-specific autistic endophenotypes induced by prenatal exposure to valproic acid involve anandamide signaling. Br J Pharmacol 175:3699–3712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mirza R, Sharma B (2019) Beneficial effects of pioglitazone, a selective peroxisome proliferator-activated receptor-γ agonist in prenatal valproic acid-induced behavioral and biochemical autistic like features in Wistar rats. Int J Dev Neurosci 76:6–16

    Article  CAS  PubMed  Google Scholar 

  • Morales P, Hurst DP, Reggio PH (2017) Molecular targets of the phytocannabinoids: a complex picture. Prog Chem Org Nat Prod 103:103–131

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moreira FA, Guimarães FS (2005) Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur J Pharmacol 512:199–205

    Article  CAS  PubMed  Google Scholar 

  • Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J et al (2010) Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry 68:368–376

    Article  PubMed  Google Scholar 

  • Mostafavi M, Gaitanis J (2020) Autism spectrum disorder and medical cannabis: review and clinical experience. Semin Pediatr Neurol 35:100833

    Article  PubMed  Google Scholar 

  • Mottron L, Duret P, Mueller S, Moore RD, Forgeot d’Arc B, Jacquemont S et al (2015) Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism. Mol Autism 6:33

    Article  PubMed  PubMed Central  Google Scholar 

  • Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65

    Article  CAS  PubMed  Google Scholar 

  • Murrie B, Lappin J, Large M, Sara G (2020) Transition of substance-induced, brief, and atypical psychoses to schizophrenia: a systematic review and meta-analysis. Schizophr Bull 46:505–516

    Article  PubMed  Google Scholar 

  • Musella A, De Chiara V, Rossi S, Cavasinni F, Castelli M, Cantarella C et al (2010) Transient receptor potential vanilloid 1 channels control acetylcholine/2-arachidonoylglicerol coupling in the striatum. Neuroscience 167:864–871

    Article  CAS  PubMed  Google Scholar 

  • Nabbout R, Gennaro E, Dalla Bernardina B, Dulac O, Madia F, Bertini E et al (2003) Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology 60:1961–1967

    Article  CAS  PubMed  Google Scholar 

  • Nackley AG, Makriyannis A, Hohmann AG (2003) Selective activation of cannabinoid CB2 receptors suppresses spinal Fos protein expression and pain behavior in a rat model of inflammation. Neuroscience 119:747–757

    Article  CAS  PubMed  Google Scholar 

  • Nardo M, Casarotto PC, Gomes FV, Guimarães FS (2014) Cannabidiol reverses the mCPP-induced increase in marble-burying behavior. Fundam Clin Pharmacol 28:544–550

    Article  CAS  PubMed  Google Scholar 

  • Nona CN, Hendershot CS, Le Foll B (2019) Effects of cannabidiol on alcohol-related outcomes: a review of preclinical and human research. Exp Clin Psychopharmacol 27:359

    Article  CAS  PubMed  Google Scholar 

  • Nutma E, Willison H, Martino G, Amor S (2019) Neuroimmunology – the past, present and future. Clin Exp Immunol 197:278–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Sullivan SE (2016) An update on PPAR activation by cannabinoids. Br J Pharmacol 173:1899–1910

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Osborne AL, Solowij N, Babic I, Lum JS, Huang XF, Newell KA, Weston-Green K (2019) Cannabidiol improves behavioral and neurochemical deficits in adult female offspring of the maternal immune activation (poly I:C) model of neurodevelopmental disorders. Brain Behav Immun 81:574–587

    Article  CAS  PubMed  Google Scholar 

  • Osborne AL, Solowij N, Babic I, Lum JS, Huang XF, Newell KA, Weston-Green K (2019) Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signaling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 95:109666

    Article  CAS  PubMed  Google Scholar 

  • Patra PH, Serafeimidou-Pouliou E, Bazelot M, Whalley BJ, Williams CM, McNeish AJ (2020) Cannabidiol improves survival and behavioral co-morbidities of Dravet syndrome in mice. Br J Pharmacol 177:2779–2792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pedrazzi JFC, Issy AC, Gomes FV, Guimarães FS, Del-Bel EA (2015) Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine. Psychopharmacology 232:3057–3065

    Article  CAS  PubMed  Google Scholar 

  • Pertwee RG (2008) Ligands that target cannabinoid receptors in the brain: From THC to anandamide and beyond. Addict Biol 13:147–159

    Article  CAS  PubMed  Google Scholar 

  • Pilorge M, Fassier C, Le Corronc H, Potey A, Bai J, De Gois S, Delaby E, Assouline B, Guinchat V, Devillard F et al (2016) Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism. Mol Psychiatry 21:936–945

    Article  CAS  PubMed  Google Scholar 

  • Piomelli D (2003) The molecular logic of endocannabinoid signaling. Nat Rev Neurosci 4:873–884

    Article  CAS  PubMed  Google Scholar 

  • Poleg S, Golubchik P, Offen D, Weizman A (2019) Cannabidiol as a suggested candidate for treatment of autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry 8:90–96

    Article  CAS  Google Scholar 

  • Ponton JA, Smyth K, Soumbasis E, Llanos SA, Lewis M, Meerholz WA, Tanguay RL (2020) A pediatric patient with autism spectrum disorder and epilepsy using cannabinoid extracts as complementary therapy: a case report. J Med Case Rep 14:1–7

    Article  Google Scholar 

  • Pretzsch CM, Freyberg J, Voinescu B, Lythgoe D, Horder J, Mendez MA et al (2019) Effects of cannabidiol on brain excitation and inhibition systems; a randomized placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder. Neuropsychopharmacology 44:1398–1405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pretzsch CM, Voinescu B, Mendez MA, Wichers R, Ajram L, Ivin G et al (2019) The effect of cannabidiol (CBD) on low-frequency activity and functional connectivity in the brain of adults with and without autism spectrum disorder (ASD). J Psychopharmacol 33:1141–1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Purcell AE, Jeon OH, Pevsner J (2001) The abnormal regulation of gene expression in autistic brain tissue. J Autism Dev Disord 31:545–549

    Article  CAS  PubMed  Google Scholar 

  • Qin M, Zeidler Z, Moulton K, Krych L, Xia Z, Smith CB (2015) Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome. Behav Brain Res 291:164–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rademacher L, Schulte-Ruther M, Hanewald B, Lammertz S (2017) Reward: from basic reinforcers to anticipation of social cues. Curr Top Behav Neurosci 30:207–221

    Article  PubMed  Google Scholar 

  • Ramaswami G, Geschwind DH (2018) Genetics of autism spectrum disorder. Handb Clin Neurol 147:321–329

    Article  PubMed  Google Scholar 

  • Renard J, Loureiro M, Rosen LG, Zunder J, de Oliveira C, Schmid S, Rushlow WJ, Laviolette SR (2016) Cannabidiol counteracts amphetamine-induced neuronal and behavioral sensitization of the mesolimbic dopamine pathway through a novel mTOR/p70S6 kinase signaling pathway. J Neurosci 36:5160–5169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rivet TT, Matson JL (2011) Review of gender differences in core symptomatology in autism spectrum disorders. Res Autism Spectr Disord 5:957–976

    Article  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Arias M, Navarrete F, Daza-Losada M, Navarro D, Aguilar MA, Berbel P, Miñarro J, Manzanares J (2013) CB1 cannabinoid receptor-mediated aggressive behavior. Neuropharmacology 75:172–180

    Article  CAS  PubMed  Google Scholar 

  • Rossignol DA, Bradstreet JJ (2008) Evidence of mitochondrial dysfunction in autism and implications for treatment. Am J Biochem Biotechnol 4:208–217

    Article  CAS  Google Scholar 

  • Rubenstein JLR, Merzenich MM (2003) Model of autism: increased ratio of excitation/inhibition in key neural systems Genes. Brain Behav 2:255–267

    CAS  Google Scholar 

  • Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043

    Article  CAS  PubMed  Google Scholar 

  • Sagar DR, Jhaveri M, Chapman V (2009) Targeting the cannabinoid system to produce Analgesia. Curr Top Behav Neurosci 1:275–287

    Article  CAS  PubMed  Google Scholar 

  • Sahin M, Sur M (2015) Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders. Science 350:6263

    Article  CAS  Google Scholar 

  • Sales AJ, Fogaça MV, Sartim AG, Pereira VS, Wegener G, Guimarães FS, Joca SRL (2019) Cannabidiol induces rapid and sustained antidepressant-like effects through increased BDNF signaling and synaptogenesis in the prefrontal cortex. Mol Neurobiol 56:1070–1081

    Article  CAS  PubMed  Google Scholar 

  • Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F (2004) Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex 14:1100–1109

    Article  PubMed  Google Scholar 

  • Satterstrom FK, Walters RK, Singh T, Wigdor EM, Lescai F et al (2019) Autism spectrum disorder and attention deficit hyperactivity disorder have a similar burden of rare protein-truncating variants. Nat Neurosci 22:1961–1965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HH, George SR, O’Dowd BF (1999) Identification and cloning of three novel human G protein-coupled receptor genes GPR52, YGPR53 and GPR55: GPR55 is extensively expressed in human brain. Mol Brain Res 64:193–198

    Article  CAS  PubMed  Google Scholar 

  • Schleider LBL, Mechoulam R, Saban N, Meiri G, Novack V (2019) Real life experience of medical cannabis treatment in autism: analysis of safety and efficacy. Sci Rep 9:1–7

    CAS  Google Scholar 

  • Schoeler T, Monk A, Sami MB, Klamerus E, Foglia E et al (2016) Continued versus discontinued cannabis use in patients with psychosis: a systematic review and meta-analysis. Lancet Psychiatry 3:215–225

    Article  PubMed  Google Scholar 

  • Schroeder JH, Desrocher M, Bebko JM, Cappadocia MC (2010) The neurobiology of autism: Theoretical applications. Res Autism Spectr Disord 4:555–564

    Article  Google Scholar 

  • Schubart CD, Sommer IEC, Fusar-Poli P, de Witte L, Kahn RS, Boks MPM (2014) Cannabidiol as a potential treatment for psychosis. Eur Neuropsychopharmacol 24:51–64

    Article  CAS  PubMed  Google Scholar 

  • Schwartz TL, Sachdeva S, Stahl SM (2012) Glutamate neurocircuitry: theoretical underpinnings in schizophrenia. Front Pharmacol 3:195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Scuderi C, De Filippis D, Iuvone T, Blasio A, Steardo A, Esposito G (2009) Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders. Phyther Res 23:597–602

    Article  CAS  Google Scholar 

  • Seeman P (2016) Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Transl Psychiatry 6:e920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sekar K, Pack A (2019) Epidiolex as adjunct therapy for treatment of refractory epilepsy: a comprehensive review with a focus on adverse effects. Research 8:F1000

    Google Scholar 

  • Servadio M, Melancia F, Manduca A, Di Masi A, Schiavi S, Cartocci V et al (2016) Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid. Transl Psychiatry 6:e902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi Q, Yang L, Shi W, Wang L, Zhou S, Guan S, Zhao M, Yang Q (2017) The novel cannabinoid receptor GPR55 mediates anxiolytic-like effects in the medial orbital cortex of mice with acute stress. Mol Brain 10:38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Silva NR, Gomes FV, Sonego AB, Silva NRD, Guimarães FS (2020) Cannabidiol attenuates behavioral changes in a rodent model of schizophrenia through 5-HT1A, but not CB1 and CB2 receptors. Pharmacol Res 156:104749

    Article  PubMed  CAS  Google Scholar 

  • Silva EADJ, Medeiros WMB, Santos JPMD, Sousa JMM, Costa FBD, Pontes KM, Borges TC et al (2022) Evaluation of the efficacy and safety of cannabidiol-rich cannabis extract in children with autism spectrum disorder: randomized, double-blind and controlled placebo clinical trial. Trends Psychiatry Psychotherapy 26:44

    Google Scholar 

  • Silvestro S, Mammana S, Cavalli E, Bramanti P, Mazzon E (2019) Use of cannabidiol in the treatment of epilepsy: efficacy and security in clinical trials. Molecules 24:1459

    Article  CAS  PubMed Central  Google Scholar 

  • Siniscalco D, Sapone A, Cirillo A, Giordano C, Maione S, Antonucci N (2012) Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? J Biomed Biotechnol 2012:480289

    Article  PubMed  PubMed Central  Google Scholar 

  • Siniscalco D, Sapone A, Giordano C, Cirillo A, de Magistris L, Rossi F, Fasano A, Bradstreet JJ, Maione S, Antonucci N (2013) Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders. J Autism Dev Disord 43:2686–2695

    Article  PubMed  Google Scholar 

  • Smith DR, Stanley CM, Foss T, Boles RG, McKernan K (2017) Rare genetic variants in theendocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans. PLoS One 12:e0187926

  • Sonego AB, Prado DS, Vale GT, Sepulveda-Diaz JE, Cunha TM, Tirapelli CR et al (2018) Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors. Brain Behav Immun 74:241–251

    Article  CAS  PubMed  Google Scholar 

  • Sorkhou M, Bedder RH, George TP (2021) The behavioral sequelae of cannabis use in healthy people: a systematic review. Front Psychiatry 12:122

    Article  Google Scholar 

  • South M, Rodgers J (2017) Sensory, emotional and cognitive contributions to anxiety in autism spectrum disorders. Front Hum Neurosci 11:20

    Article  PubMed  PubMed Central  Google Scholar 

  • Stark T, Di Bartolomeo M, Di Marco R, Drazanova E, Platania CBM, Iannotti FA et al (2020) Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment. Biochem Pharmacol 177:114004

    Article  CAS  PubMed  Google Scholar 

  • Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K et al (1995) 2-arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97

    Article  CAS  PubMed  Google Scholar 

  • Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K et al (2013) Microglial activation in young adults with autism spectrum disorder. Arch Gen Psychiatry 70:49–58

    Google Scholar 

  • Swanson LW, Sawchenko PE (1983) Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 6:269–324

    Article  CAS  PubMed  Google Scholar 

  • Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB 1 and CB 2 receptor agonists in vitro. Br J Pharmacol 150:613–623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toscano CVA, Barros L, Lima AB, Nunes T, Carvalho HM, Gaspar JM (2021) Neuroinflammation in autism spectrum disorders: exercise as a “pharmacological” tool. Neurosci Biobehav Ver 129:63–74

    Article  CAS  Google Scholar 

  • Trazzi S, Steger M, Mitrugno VM, Bartesaghi R, Ciani E (2010) CB1 cannabinoid receptors increase neuronal precursor proliferation through AKT/glycogen synthase kinase-3beta/beta-catenin signaling. J Biol Chem 285:10098–10109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valvassori SS, Elias G, De Souza B, Petronilho F, Dal-Pizzol F, Kapczinski F et al (2011) Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania. J Psychopharmacol 25:274–279

    Article  CAS  PubMed  Google Scholar 

  • Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57:67–81

    Article  CAS  PubMed  Google Scholar 

  • Volkmar FR, Lord C, Bailey A, Schultz RT, Klin A (2004) Autism and pervasive developmental disorders. J Child Psychol Psychiatry Allied Discip 45:135–170

    Article  Google Scholar 

  • Walzer M, Bekersky I, Blum RA, Tolbert D (2012) Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes. Pharmacotherapy 32:340–353

    Article  CAS  PubMed  Google Scholar 

  • Warren Z et al (2012) Therapies for children with autism spectrum disorders. Comp Eff Rev 85:878–879

    Google Scholar 

  • Watson S, Chambers D, Hobbs C, Doherty P, Graham A (2008) The endocannabinoid receptor, CB1, is required for normal axonal growth and fasciculation. Mol Cell Neurosci 38:89–97

    Article  CAS  PubMed  Google Scholar 

  • Wei D, Lee D, Cox CD, Karsten CA, Peñagarikano O, Geschwind DH et al (2015) Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci U S A 112:14084–14089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei D, Dinh D, Lee D, Li D, Anguren A, Moreno-Sanz G et al (2016) Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment. Cannabis Cannabinoid Res 1:81–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei D, Allsop S, Tye K, Piomelli D (2017) endocannabinoid signaling in the control of social behavior. Trends Neurosci 40:385–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winden KD, Ebrahimi-Fakhari D, Sahin M (2018) Abnormal mTOR activation in autism. Annu Rev Neurosci 41:1–23

    Article  CAS  PubMed  Google Scholar 

  • Yamashita Y, Fujimoto C, Nakajima E, Isagai T, Matsuishi T (2003) Possible association between congenital cytomegalovirus infection and autistic disorder. J Autism Dev Disord 33:455–459

    Article  PubMed  Google Scholar 

  • Yang L, Rozenfeld R, Wu D, Devi LA, Zhang Z, Cederbaum A (2014) Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy. Free Radic Biol Med 68:260–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young LJ, Barrett CE (2015) Can oxytocin treat autism? Science 347:825–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zamberletti E, Gabaglio M, Parolaro D (2017) The endocannabinoid system and autism spectrum disorders: insights from animal models. Int J Mol Sci 18:1916

    Article  PubMed Central  CAS  Google Scholar 

  • Zendulka O, Dovrtelová G, Nosková K, Turjap M, Šulcová A, Hanuš L, Juřica J et al (2016) Cannabinoids and cytochrome P450 interactions. Curr Drug Metab 17:206–226

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Hoffert C, Vu HK, Groblewski T, Ahmad S, O’Donnell D (2003) Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci 17:2750–2754

    Article  PubMed  Google Scholar 

  • Zheng Z, Zheng P, Zou X (2018) Association between schizophrenia and autism spectrum disorder: a systematic review and meta-analysis. Autism Res 11:1110–1119

    Article  PubMed  Google Scholar 

  • Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG (1982) Action of cannabidiol on the anxiety and other effects produced by δ9-THC in normal subjects. Psychopharmacology 76:245–250

    Article  CAS  PubMed  Google Scholar 

  • Zuardi AW, Antunes Rodrigues J, Cunha JM (1991) Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology 104:260–264

    Article  CAS  PubMed  Google Scholar 

  • Zuardi AW, Cosme RA, Graeff FG et al (1993) Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacoly 7:82–88

    Article  CAS  Google Scholar 

  • Zwaigenbaum L, Bauman ML, Fein D, Pierce K, Buie T, Davis PA et al (2015) Early screening of autism spectrum disorder: recommendations for practice and research. Pediatrics 136:S41–S59

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Lucas Prota Crippa for preparing the art in Fig. 2

Funding

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and by the Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM; CNPq/FAPESP; 2008/09009–2). JAC received a grant from the University Global Partnership Network (UGPN) – Global Priorities in Cannabinoid Research Excellence Program. ACC, FSG, EADB, JAC, JEH, and AWZ are recipients of CNPq research fellowships. The authors appreciate the financial support from Fapesp, Capes, and CNPq.

Author information

Authors and Affiliations

  1. Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    João F. C. Pedrazzi, Daniel A. Lima, Jaime E. C. Hallak, Antônio W. Zuardi, Elaine A. Del-Bel & José A. S. Crippa

  2. Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, 21040-900, Brazil

    Frederico R. Ferreira

  3. Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Danyelle Silva-Amaral

  4. Department of Morphology, Physiology, and Basic Pathology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Elaine A. Del-Bel

  5. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Francisco S. Guimarães, Karla C. M. Costa & Alline C. Campos

  6. Graduate Program in Child and Adolescent Health, Neuropediatric Center of the Hospital of Clinics (CENEP), Federal University of Paraná, Curitiba, Paraná, Brazil

    Ana C. S. Crippa

Authors
  1. João F. C. Pedrazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frederico R. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Danyelle Silva-Amaral
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel A. Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jaime E. C. Hallak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antônio W. Zuardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elaine A. Del-Bel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francisco S. Guimarães
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Karla C. M. Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alline C. Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ana C. S. Crippa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. José A. S. Crippa
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors have contributed to the writing of this review.

Corresponding author

Correspondence to João F. C. Pedrazzi.

Ethics declarations

Conflict of interest

JAC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) – National Health and Medical Research Council (NHMRC). JAC and JEH have received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm. JAC, JEH, FSG, and AWZ are co-inventors of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: W.O./2014/108899. International Application No.: PCT/IL2014/050023,” Def. U.S. number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimarâes FS, Crippa JAS, Breuer A). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JAC, JEH, FSG, and AWZ are co-inventors of the patent “Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same,” INPI on September 16, 2016 (BR 112018005423–2). JAC and JECH have received personal consultation fees from BSPG-Pharm, and PurMed Global in the past. JAC received speaking fees from Torrent, Green Care Store and Janssen. The other authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pedrazzi, J.F.C., Ferreira, F.R., Silva-Amaral, D. et al. Cannabidiol for the treatment of autism spectrum disorder: hope or hype?. Psychopharmacology 239, 2713–2734 (2022). https://doi.org/10.1007/s00213-022-06196-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-022-06196-4

Keywords

Search

Navigation