Table 2.
(a). Methodological quality of animal studies investigating ASD and psychosis as a function of the eCB system. (b). Methodological quality of human studies investigating ASD and psychosis as a function of the eCB system.
| (a) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Study | Study Design | Defined Study Population | Age | Gender | Control | eCB System Involvement | ASD Involvement | Psychosis Involvement | Statistical Analyses | Funding or Sponsorship |
| Onaivi et al., (2011) (USA) [25] | √ Analytic, observational, interventional | √ BTBR, C57, S129 mice | √ Adult | √ Male and female | √ VHI; C57; S129 | √ 1. THC single administration: (a) 1 mg/kg IP; (b) 10 mg/kg IP; 2. CB2 gene expression | √ Idiopathic animal model | √ Behavioral features | √ Student’s t-test; ANOVA; Tukey’s test | √ |
| Anderson et al., (2015) (USA) [26] | √ Analytic, observational | √ NBF mice | √ 1. mRNA measurements: P30;2. Neuron cultures from newborn NBF: DIV 3–4 to DIV 14–16 | X | √ ΔCre | √ eCBs/AEs signaling | √ Genetically induced animal model | √ Genetically induced animal model | √ Student’s t-test | √ |
| Doenni et al., (2016) (Canada) [27] | √ Analytic, observational, interventional | √ Sprague Dawley rats | √ P14 and P40 | √ Male and female | √ SAL | √ 1. Double eCBs/AEs levels assessment (P14, P40); 2. FAAHi single administration (oral, BLA injection) |
√ Inflammatory-induced animal model; Behavioral features | √ Inflammatory-induced animal model; Behavioral features | √ F-test; Bonferroni’s post hoc test; Student’s t-test; ANOVA | √ |
| Schrott et al., (2019) (USA) [28] | √ Analytic, observational, interventional | √ Sprague Dawley rats | √ 9 weeks | √ Male | √ VHI | √ THC daily administration: 4 mg/kg SC, 28 days | √ Genetic liability | √ Intergenerational genetic liability | √ Student’s t-test; Bonferroni’s post hoc test; Pearson correlation | √ |
| Schrott et al., (2020) (USA) [29] | √ Analytic, observational, interventional | √ Sprague Dawley rats | √ Young adult | √ Male | √ VHI | √ THC daily administration: (a) 2 mg/kg oral, 12 days; (b) 4 mg/kg SC, 28 days | √ Genetic liability | √ Genetic liability | √ Student’s t-test; Bonferroni’s post hoc test; Pearson correlation; Fisher’s exact test | √ |
| Wanner et al., (2020) (USA) [30] | √ Analytic, observational, interventional | √ C57 mice | √ 14 weeks | √ Male | √ VHI | √ CBD daily administration: 20 mg/kg oral, 14 days | √ Genetic liability | √ Genetic liability | √ chi-square test; Fisher’s exact test; Benjamini-Hochberg adjusted p-values | √ |
| (b) | ||||||||||
| Study | Study Design | Defined Study Population | Age | Gender | Control | eCB System Involvement | ASD Involvement | Psychosis Involvement | Statistical Analyses | Funding or Sponsorship |
| Stringer et al., (2016) (Netherlands) [31] | √ Meta-analysis | √ Lifetime cannabis use | √ 16–87 years (average 34 years) | √ Male and female (30–66%) | √ 4 independent replication samples | √ Cannabis exposure | √ Genetic liability | √ Genetic liability | √ Logistic regression | √ |
| Aran et al., (2018) (Israel) [32] | √ Analytic, observational, interventional | √ DSM-5 (77% low cognitive functioning according to ADOS or CARS) | √ 5–17 years [11.8 (± 3.5)] | √ Male (83%) and female | X | √ CBD-rich treatment (CBD:THC = 20:1, sublingual administration), 2–3 times per day, up to 10 mg/kg/die | √ Diagnosed patients | √ Adverse event | √ Mann–Whitney U test; Spearman’s rho correlation; Pearson correlation | X |
| Guennewig et al., (2018) (Australia) [33] | √ Analytic, observational, interventional | √ General population: hiPSC-derived neurons |
X | X | √ Untreated; SCZ hiPSC- derived neurons |
√ 1. (a) Acute THC-exposure (1 μM for 24 h); (b) Chronic THC-exposure (50 nM; 5 treatments over 7 days); 2. Genetic liability |
√ Genetic liability | √ Genetic liability; SCZ-like biological alterations | √ ANOVA; Tukey’s test for multiple comparisons |
√ |
| Legge et al., (2019) (Netherlands) [34] | √ Analytic, observational | √ MHQ | √ 64 (± 7.6) years | √ Male (44%) and female | √ nMHQ | √ Genetic liability | √ Genetic liability | √ 1. Psychotic symptoms; 2. Genetic liability |
√ Logistic regression; Bonferroni’s correction | √ |
| Schrott et al., (2019) (USA) [28] | √ Analytic, observational | √ General population: 1. Screened for (a) past 6-month CU; (b) UDS results; (c) [THCCOOH] in urine;2. Conceptal tissues from elective pregnancy termination |
√ 1. 18–40 years; 2. 67–122 gestational days | √ Male and female | √ Gene-based tests on sperm: Non-users | √ Cannabis exposure | √ Genetic liability | √ Genetic liability | √ Student’s t-test; Bonferroni’s post hoc test; Pearson correlation | √ |
| Schrott et al., (2020) (USA) [29] | √ Analytic, observational | √ General population: screened for 1. past 6-month CU; 2. UDS results; 3. [THCCOOH] in urine | √ 18–40 years | √ Male | √ Non-users | √ Cannabis exposure | √ Genetic liability | √ Genetic liability | √ Student’s t-test; Bonferroni’s post hoc test; Pearson correlation; Fisher’s exact test | √ |
| Al-Soleiti et al., (2021) (Jordan) [35] | √ Case report | √ DSM-5 | √ 1. 20 years old; 2. 23 years old; 3. 23 years old | √ Male | X | √ 1. 2-months daily CBD oil (<0.03 % THC); 2. Self-prescribed sativa/indica mixtures (20 % THC); 3. Marijuana consumption (until 90% THC) |
√ Diagnosed patients | √ Adverse event | X | X |
| Powell et al., (2021) (USA) [36] | √ Analytic, observational | √ General population: 1. hiPSC derived iDANs; 2. Post-mortem samples |
√ Post-mortem samples: adult brains | X | √ hiPSC derived 1. iGANs; 2. iGLUTs |
√ Genetic liability for CUD | √ Genetic liability | √ Genetic liability | √ ANOVA; Tukey’s test for multiple comparisons; Bonferroni’s post hoc test |
√ |
eCB, endocannabinoid; ASD, Autism Spectrum Disorder; BTBR, BTBR T+tf/J mice; C57, C57BL/6 mice; S129, 129S1/SvImJ mice; VHI, vehicle; THC, Δ9-tetrahydrocannabinol; mg/kg, milligrams per kilogram; IP, intraperitoneal; ANOVA, analysis of variance; NBF, Neurexin β-floxed; P30, Postnatal day 30; DIV, Days in vitro; ΔCre, truncate Cre-ricombinase; AEs, acylethanolamines; P14, Postnatal day 14; P40, Postnatal day 40; SAL, saline; FAAHi, FAAH inhibitor PF-04457845; BLA, basolateral amygdala; SC, subcutaneous; CBD, cannabidiol; DSM-5, The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ADOS, Autism Diagnostic Observation Schedule; CARS, Childhood Autism Rating Scale; hiPSC, Human Induced Pluripotent Stem Cell; SCZ, schizophrenia; μM, micromolar; h, hour/hours; nM, nanomolar; MHQ, Mental Health Questionnaire; nMHQ, individuals who provided a negative response to all psychotic experience symptom questions at MHQ; UDS, Urine Drugs Screening; THCCOOH, carboxy-Δ9-tetrahydrocannabinol; iDANs, induced dopaminergic neurons; SEGs, Specifically Expressed Genes; iGANs, induced GABAergic neurons; iGLUTs, induced glutamatergic neurons; CUD, Cannabis Use Disorder; <, lower than.