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Cited by 233Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersChild Nutrition and Feeding Issues

An Update on Psychopharmacological Treatment of Autism Spectrum Disorder

Open access
Aishworiya, Ramkumar, Valica, Tatiana, Hagerman, Randi, Restrepo, Bibiana·2022·Neurotherapeutics
DOI 10.1007/s13311-022-01183-1PMC PMC9130393
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Abstract

While behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review updates psychopharmacological treatment for autism spectrum disorder (ASD), emphasizing that behavioral interventions remain the mainstay while medications mainly address comorbid symptoms. It reviews established agents and emerging targeted treatments, using Fragile X syndrome (FXS) as a model for genetic-subtype-specific approaches.

Key findings

  • ASD prevalence is estimated at 1 in 44 people; approximately two-thirds of autistic adolescents have been treated with psychotropic medications, and co-occurring mental health conditions are reported in approximately 70% of autistic individuals. Polypharmacy rates range from 12 to 35% depending on study type.
  • FDA-approved medications for ASD irritability are risperidone (children older than 5 years) and aripiprazole (children 6 to 17 years); both reduce irritability and, to a lesser degree, repetitive behaviors, but long-term efficacy and safety are not established.
  • In the largest methylphenidate crossover trial, approximately 50% of children with ASD responded based on the Aberrant Behavior Checklist hyperactivity subscale, with effect sizes from 0.20 to 0.54 depending on dose and rater; 6 of 66 children (9.1%) discontinued due to adverse effects.
  • Emerging targeted treatments show mixed or subtype-specific results: bumetanide did not improve core ASD symptoms on the SRS-2 in a phase 2 trial but improved repetitive behavior; oxytocin evidence remains inconclusive for long-term core symptom benefit; and in a 32-child FXS lovastatin trial, parent-implemented language intervention alone produced as much improvement as lovastatin plus intervention.

Methods

  • Narrative review of current psychopharmacological treatment in ASD, covering established medications for comorbidities and emerging targeted treatments, with FXS discussed as the most common genetic disorder leading to ASD.
  • A systematic literature search was completed on Medline, Scopus, and Embase using key terms including “autism,” “autism spectrum disorder,” “targeted treatments,” “pharmacological therapy,” and “management.”
  • The paper reviews selected clinical trials, meta-analyses, and animal-model evidence but does not report search dates, inclusion/exclusion criteria, or formal quality appraisal.

Limitations

  • Stated in the paper: current evidence has established only behavioral treatments as the mainstay for core ASD symptoms; research in behavioral interventions for adults with ASD is still limited; alpha-2-agonist studies in ASD are limited and have small sample sizes; long-term beneficial effects of oxytocin are not conclusively established; bumetanide evidence is inconclusive; and long-term efficacy/safety of atypical antipsychotics for irritability is not established.
  • Evident from the text: this is a narrative review without a formal systematic review protocol, risk-of-bias assessment, or meta-analysis, and many cited studies are small, open-label, or use parent-reported outcomes.
  • Evident from the text: the review does not provide a comprehensive accounting of all searched literature, and several emerging treatments are described with ongoing or unreported trials, limiting current conclusions.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s13311-022-01183-1

Cites

149 of 149 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 157 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    The genetic subtype of ASD makes a difference in response to treatment.

    “Therefore, the genetic subtype of ASD makes a difference in response to treatment and all children diagnosed with ASD must have genetic testing including Fragile X DNA testing and a CGH array for starters and subsequent”
    Quote in the paperSubstantial claim
  • Premisecitation

    A similar study in young children ages 2 to 6 with idiopathic ASD (without FXS) treated with low-dose sertraline did not demonstrate a benefit of sertraline compared to placebo.

    “However, a similar study in young children ages 2 to 6 with idiopathic ASD (without FXS) treated with low-dose sertraline did not demonstrate a benefit of sertraline compared to placebo [38].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Potter, 2019, A randomized controlled trial of sertraline in young children with autism spectrum disorder, Front Psych source

      Not checked in the free run.

  • Premisecitation

    A retrospective study of children with FXS (ages 12 to 50 months) demonstrated improvement in the trajectory of both receptive and expressive language measures on the Mullen Scales of Early Learning (MSEL) in those treated with low-dose sertraline vs those who did not receive sertraline.

    “A retrospective study of children with FXS (ages 12 to 50 months) demonstrated improvement in the trajectory of both receptive and expressive language measures on the Mullen Scales of Early Learning (MSEL) in those treated with low-dose sertraline vs those who did not receive sertraline [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Indah Winarni T, Chonchaiya W, Adams E, Au J, Mu Y, Rivera SM, et al. Sertraline may improve language developmental trajectory in young children with fragile x syndrome: a retrospective chart review. Autism research and treatment. 2012;2012. source

      Not checked in the free run.

  • Premisecitation

    In a controlled trial of sertraline in children ages 2 to 6 with FXS (60% also had ASD), those treated with sertraline demonstrated greater improvement in motor and visual subtests and the Cognitive T score on the MSEL compared to those on placebo.

    “Those treated with sertraline demonstrated greater improvement in motor and visual subtests and the Cognitive T score on the MSEL compared to those on placebo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Hess, 2016, A randomized, double-blind, placebo-controlled trial of low-dose sertraline in young children with fragile X syndrome, Journal of developmental and behavioral pediatrics: JDBP source

      Not checked in the free run.

  • Premisecitation

    Risperidone and aripiprazole are linked to more serious side effects including dyslipidemia, hyperglycemia, metabolic syndrome, and extrapyramidal symptoms or drug-induced movement disorders.

    “They are also linked to more serious side effects including dyslipidemia, hyperglycemia, metabolic syndrome, and extrapyramidal symptoms or drug-induced movement disorders.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] McCracken, 2002, Risperidone in children with autism and serious behavioral problems, N Engl J Med source

      Not checked in the free run.

    • cites [41] Owen, 2009, Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder, Pediatrics source

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  • May combine two claims. 51
  • Classified as probably not a substantial claim. 8
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Two medications are approved by the FDA for the treatment of irritability associated with ASD: risperidone, approved for children older than 5 years of age, and aripiprazole, approved for children 6 to 17 years of age.

    “There are two medications approved by the FDA for the treatment of irritability associated with ASD: risperidone, approved for children older than 5 years of age [40], and aripiprazole, approved for children 6 to 17 years of age [41]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [40] McCracken, 2002, Risperidone in children with autism and serious behavioral problems, N Engl J Med source

      Not checked in the free run.

    • cites [41] Owen, 2009, Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder, Pediatrics source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years.

    “several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mandell et al. reported that 56% were prescribed at least one psychotropic medication and 20% were prescribed three or more.

    “Mandell et al. reported that 56% were prescribed at least one psychotropic medication and 20% were prescribed three or more [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Mandell, 2008, Psychotropic medication use among Medicaid-enrolled children with autism spectrum disorders, Pediatrics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Risperidone and aripiprazole share similar safety profiles; the most common side effects include fatigue, increased appetite, GI symptoms, hyperprolactinemia, weight gain, and sedation, and less commonly activation including restlessness and akathisia.

    “They also share similar safety profiles; the most common side effects include fatigue, increased appetite, GI symptoms, hyperprolactinemia, weight gain, and sedation, and less commonly activation including restlessness and akathisia.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] McCracken, 2002, Risperidone in children with autism and serious behavioral problems, N Engl J Med source

      Not checked in the free run.

    • cites [41] Owen, 2009, Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder, Pediatrics source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Co-occurring mental health conditions are reported in approximately 70% of autistic individuals.

    “Co-occurring mental health conditions have been reported in approximately 70% of autistic individuals ranging from attention deficit and hyperactivity disorder (ADHD), irritability, aggression, mood, and anxiety issues [8, 25, 26].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] Simonoff, 2008, Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample, J Am Acad Child Adolesc Psychiatry source

      Not checked in the free run.

    • cites [25] Feroe, 2021, Medication use in the management of comorbidities among individuals with autism spectrum disorder from a large nationwide insurance database, JAMA Pediatr source

      Not checked in the free run.

    • cites [26] Levy, 2010, Autism spectrum disorder and co-occurring developmental, psychiatric, and medical conditions among children in multiple populations of the United States, Journal of developmental and behavioral pediatrics : JDBP source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a randomized controlled trial of sulforaphane lasting 15 weeks followed by an open label trial for another 15 weeks in 57 children ages 3 to 12 years, the primary outcome measure, the Ohio Autism Clinical Impressions Scale, did not improve significantly in those on sulforaphane, but a secondary measure, the ABC, did significantly improve on sulforaphane vs placebo, while the SRS did not.

    “Although the primary outcome measure, the Ohio Autism Clinical Impressions Scale, did not improve significantly in those on sulforaphane, a secondary measure, the ABC, did significantly improve on sulforaphane vs placebo but the SRS did not.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Zimmerman, 2021, Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder, Molecular autism

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A specific systematic review of four-crossover trials in autistic children (113 participants) age 5 to 13 years found low-quality evidence that short-term treatment with methylphenidate may improve hyperactivity and inattention in children with ASD, and the only significant adverse side effect was reduced appetite as rated by parents; however, there was no evidence of impact on core ASD symptoms或

    “Specific systematic review of four-crossover trials in autistic children (113 participants) age 5 to 13 years found low-quality evidence that short-term treatment with methylphenidate may improve hyperactivity and inattention in children with ASD, and the only significant adverse side effect was reduced appetite as rated by parents; however, there was no evidence of impact on core ASD symptoms or”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Sturman N, Deckx L, van Driel ML. Methylphenidate for children and adolescents with autism spectrum disorder. Cochrane Database of Systematic Reviews. 2017(11). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the largest crossover trial, approximately 50% of children with ASD responded to methylphenidate based on the hyperactivity subscale of the Aberrant Behavior Checklist (ABC); the effect size ranged from 0.20 to 0.54, depending upon dose and rater, with greater improvement at higher doses.

    “In the largest crossover trial, approximately 50% of children with ASD responded to methylphenidate based on the hyperactivity subscale of the Aberrant Behavior Checklist (ABC); the effect size ranged from 0.20 to 0.54, depending upon dose and rater, with greater improvement at higher doses”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Posey, 2007, Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders: an analysis of secondary measures, Biol Psychiat source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a systematic review and network meta-analysis of 81 published and unpublished randomized trials in >10,000 neurotypical children, amphetamines were slightly more efficacious than methylphenidate in reducing clinician-rated core symptoms of ADHD at approximately 12 weeks; however, amphetamines were less tolerable than placebo and methylphenidate was better tolerated than amphetamines.

    “In a systematic review and network meta-analysis that included 81 published and unpublished randomized trials in > 10,000 neurotypical children, amphetamines were slightly more efficacious than methylphenidate in reducing clinician-rated core symptoms of ADHD at approximately 12 weeks; however, amphetamines were less tolerable than placebo and methylphenidate was better tolerated than amphetamines”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Cortese, 2018, Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis, The Lancet Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NAC was well tolerated although an occasional patient did not like the taste or had minimal gastrointestinal side-effects.

    “NAC was well tolerated although an occasional patient did not like the taste or had minimal gastrointestinal side-effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Hardan, 2012, A randomized controlled pilot trial of oral N-acetylcysteine in children with autism, Biol Psychiat source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Sulforaphane is a naturally occurring isothiocyanate found in broccoli and other cruciferous vegetables.

    “Sulforaphane is a naturally occurring isothiocyanate (found in broccoli and other cruciferous vegetables) [63–65].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [63] Sestili P, Fimognari C. Cytotoxic and antitumor activity of sulforaphane: the role of reactive oxygen species. Biomed Res Int. 2015;2015:402386. source

      Not checked in the free run.

    • cites [64] Liang, 2019, Sulforaphane as anticancer agent: a double-edged sword? Tricky balance between effects on tumor cells and immune cells, Adv Biol Regul source

      Not checked in the free run.

    • cites [65] Kamal, 2020, Sulforaphane as an anticancer molecule: mechanisms of action, synergistic effects, enhancement of drug safety, and delivery systems, Arch Pharm Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a recent review of nine controlled trials of 430 children with ASD comparing methylphenidate, atomoxetine, and guanfacine, methylphenidate and atomoxetine had superior effects than placebo in addressing ADHD symptoms; however, the response for hyperactivity symptoms was less than observed in neurotypical populations with both medications.

    “In a recent review of nine controlled trials of 430 children with ASD comparing the response between methylphenidate, atomoxetine, and guanfacine, methylphenidate and atomoxetine had superior effects than placebo in addressing ADHD symptoms; however, the response for hyperactivity symptoms was less than observed in neurotypical populations with both medications [57].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Rodrigues, 2021, Practitioner Review: Pharmacological treatment of attention-deficit/hyperactivity disorder symptoms in children and youth with autism spectrum disorder: a systematic review and meta-analysis, J Child Psychol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NAC works by two mechanisms to lower the E:I imbalance; it lowers glutamatergic neurotransmission, and the cysteine leads to an increase in glutathione synthesis which is an important antioxidant.

    “NAC works by two mechanisms to lower the E:I imbalance; it lowers glutamatergic neurotransmission, and the cysteine leads to an increase in glutathione synthesis which is an important antioxidant.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Hardan, 2012, A randomized controlled pilot trial of oral N-acetylcysteine in children with autism, Biol Psychiat source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melatonin is usually well tolerated and has a low incidence of side effects.

    “clinicians may recommend the use of melatonin which is usually well tolerated and has a low incidence of side effects [59].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Buckley, 2020, Practice guideline: Treatment for insomnia and disrupted sleep behavior in children and adolescents with autism spectrum disorder: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology, Neurology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Additional improvements were seen in stereotypic behaviors with significance reached on the RBS-S Stereotypies subscale (p < 0.014) and the SRS Autism Mannerisms subscale (p < 0.045) for those treated with NAC vs placebo.

    “Additional improvements were seen in stereotypic behaviors with significance reached on the RBS-S Stereotypies subscale (p < 0.014) and the SRS Autism Mannerisms subscale (p < 0.045) for those treated with NAC vs placebo [62].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Hardan, 2012, A randomized controlled pilot trial of oral N-acetylcysteine in children with autism, Biol Psychiat source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Amphetamines are usually slightly more efficacious than methylphenidate derivatives, which are usually better tolerated.

    “There are two main stimulant families: the amphetamines are usually slightly more efficacious than the methylphenidate derivates which are usually better tolerated [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Cortese, 2018, Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis, The Lancet Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Data from randomized trials, systematic reviews, and meta-analyses show that atomoxetine and alpha-2-adrenergic agonists are more effective than placebo in reducing the core symptoms of ADHD, but as a class, they are less effective than stimulants.

    “Data from randomized trials, systematic reviews, and meta-analyses show that atomoxetine and alpha-2-adrenergic agonists are more effective than placebo in reducing the core symptoms of ADHD, but as a class, they are less effective than stimulants [49, 55, 56].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [49] Cortese, 2018, Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis, The Lancet Psychiatry source

      Not checked in the free run.

    • cites [55] Connor, 1999, A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder, J Am Acad Child Adolesc Psychiatry source

      Not checked in the free run.

    • cites [56] Hirota, 2014, Alpha-2 agonists for attention-deficit/hyperactivity disorder in youth: a systematic review and meta-analysis of monotherapy and add-on trials to stimulant therapy, J Am Acad Child Adolesc Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Baseline sleep problems do not appear to predict stimulant-related sleep problems and may improve with stimulant therapy.

    “Baseline sleep problems do not appear to predict stimulant-related sleep problems and may improve with stimulant therapy [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Becker, 2016, Effects of methylphenidate on sleep functioning in children with attention-deficit/hyperactivity disorder, Journal of developmental and behavioral pediatrics: JDBP source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sulforaphane can penetrate the blood brain barrier and induces the Nrf2 signaling cascade that stimulates the expression of more than 200 genes that are antioxidants and involved in detoxification and neuroprotection in the CNS.

    “Sulforaphane is a sulfur-rich dietary phytochemical which can penetrate the blood brain barrier, and it subsequently induces the nuclear factor erythroid 2 related factor 2 (Nrf2) signaling cascade that stimulates the expression of more than 200 genes that are antioxidants and involved in detoxification and neuroprotection in the CNS [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Uddin MS, Al Mamun A, Jakaria M, Thangapandiyan S, Ahmad J, Rahman MA, et al. Emerging promise of sulforaphane-mediated Nrf2 signaling cascade against neurological disorders. Science of the Total Environment. 2020;707:135624. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Sulforaphane is an antioxidant, anti-inflammatory, and mitochondrial protective agent that has been studied in several animal models and humans with neurodegenerative and neurodevelopmental disorders.

    “Sulforaphane is an antioxidant, anti-inflammatory, and mitochondrial protective agent that has been studied in several animal models and humans with neurodegenerative and neurodevelopmental disorders [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Jardim, 2020, Effects of sulforaphane on brain mitochondria: mechanistic view and future directions, J Zhejiang Univ Sci B source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intranasal OXT leads to increased activation in brain regions involved in perceiving and thinking about social-emotional information and enhances effective connectivity between nodes of the brain's reward and socioemotional processing systems.

    “At the neural networks level, it has been shown that intranasal OXT leads to increased activation in the brain regions known to be involved in perceiving and thinking about social-emotional information and enhances effective connectivity between nodes of the brain’s reward and socioemotional processing systems [87, 88].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [87] Gordon, 2016, Intranasal oxytocin enhances connectivity in the neural circuitry supporting social motivation and social perception in children with autism, Sci Rep source

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    • cites [88] Gordon, 2013, Oxytocin enhances brain function in children with autism, Proc Natl Acad Sci source

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  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In a study by Mazahery et al. in 111 children with ASD ages 2.5 to 8 years randomized to placebo, Vitamin D 2000 IU/day, omega-3 722 mg/day, or both interventions for 1 year, those on both treatments had a significant reduction in their primary outcome measure, irritability on the ABC subscale (p < 0.001) compared to placebo, and those treated with vitamin D alone also had a reduction in irritancy

    “A more recent study was carried out by Mazahery et al. [73] in 111 children with ASD ages 2.5 to 8 years, and they were randomized to placebo, Vitamin D 2000 IU/day, or omega-3 722 mg/day or both interventions for 1 year of treatment. Seventy-three patients completed a year of therapy, and those on both treatments had a significant reduction in their primary outcome measure, irritability on the”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Mazahery, 2019, A randomised controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of irritability and hyperactivity among children with autism spectrum disorder, J Steroid Biochem Mol Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There were no significant adverse events and the sulforaphane supplement was well tolerated.

    “There were no significant adverse events and the supplement was well tolerated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Zimmerman, 2021, Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder, Molecular autism

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent meta-analysis suggests overall beneficial effects of OXT on social symptoms of ASD, although it included both children and adults.

    “Nonetheless, as illustrated by a recent meta-analysis, there does seem to be overall beneficial effects of OXT on social symptoms of ASD, although this review included both children and adults [90].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Huang Y, Huang X, Ebstein RP, Yu R. Intranasal oxytocin in the treatment of autism spectrum disorders: a multilevel meta-analysis. Neuroscience & Biobehavioral Reviews. 2021. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There have been generally positive results of OXT in adults with ASD, with trials showing improvements in repetitive behaviors, social reciprocity, and emotion recognition.

    “There have been generally positive results of OXT in adults with ASD, with trials showing improvements in repetitive behaviors, social reciprocity, and emotion recognition [75–77].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [75] Anagnostou, 2012, Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial, Molecular autism source

      Not checked in the free run.

    • cites [76] Egawa, 2015, Resequencing and association analysis of OXTR with autism spectrum disorder in a Japanese population, Psychiatry Clin Neurosci source

      Not checked in the free run.

    • cites [77] Yamasue, 2020, Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial, Mol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the same trial, there were significant improvements in biomarkers including glutathione redox status, mitochondrial respiration, inflammatory markers, and heat shock proteins on sulforaphane vs placebo, and these improvements correlated with improvements on the ABC.

    “In addition, there were significant improvements in the biomarkers including the glutathione redox status, mitochondrial respiration, inflammatory markers, and heat shock proteins on sulforaphane vs placebo, and these improvements correlated with improvements on the ABC.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Zimmerman, 2021, Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder, Molecular autism

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The role of OXT thus far has been limited to its immediate effect after administration and hence is not a single treatment option for ASD.

    “The role of OXT thus far has been limited to its immediate effect after administration and hence is not a single treatment option for ASD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CBD acts as a positive allosteric modulator at GABAA receptors, and controlled trials have shown that CBD in the form of Epidiolex is an effective anticonvulsant in Dravet syndrome and Lennox-Gastaut syndrome.

    “CBD has also been shown to act as a positive allosteric modulator at GABAA receptors, and controlled trials have shown that CBD in the form of Epidiolex is an effective anticonvulsant in Dravet syndrome and Lennox-Gastaut syndrome [120].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Thiele, 2018, Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial, The Lancet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CBD has numerous therapeutic effects including treatment of anxiety, pain, nausea, and motor deficits including tremor in Parkinson's disease.

    “CBD is the non-psychotropic component of marijuana, and there are numerous therapeutic effects of this drug including treatment of anxiety, pain, nausea, and motor deficits including the tremor in Parkinson’s disease [116].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Patricio F, Morales-Andrade AA, Patricio-Martínez A, Limón ID. Cannabidiol as a therapeutic target: Evidence of its neuroprotective and neuromodulatory function in parkinson's disease. Frontiers in Pharmacology. 2020;11. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In reviewed studies of individuals with ASD treated with CBD, benefits were seen in irritability, sleep disorders, tantrums, and anxiety, although the preparations studied had both CBD and variable levels of THC.

    “Studies of individuals with ASD treated with CBD and open label trials of CBD are reviewed by Nezgovorva et al. [123]; however, the preparations studied have both CBD and variable levels of THC, although in general, benefits were seen in irritability, sleep disorders, tantrums, and anxiety.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Nezgovorva, 2022

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    Premisecitation

    Studies of lovastatin treatment in the FXS knock out (KO) mouse rescued excess protein synthesis and also epilepsy.

    “Studies of lovastatin treatment in the FXS knock out (KO) mouse rescued excess protein synthesis and also epilepsy [113].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Osterweil, 2013, Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome, Neuron source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The BRIGHT study, an open label study of children ages 3 to 17 with ASD lasting 14 weeks, showed benefits in most outcome measures including the ABC and measures of anxiety.

    “The BRIGHT study was an open label study of children ages 3 to 17 with ASD lasting 14 weeks, and benefits were seen in most outcome measures including the ABC and measures of anxiety [124].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Heussler H, Michael Duhig TH, Carol O'Neill, Donna Gutterman, Joseph M. Palumbo, Terri Sebree. Longer term tolerability and efficacy of ZYN002 cannabidiol transdermal gel in children and adolescents with autism spectrum disorder (ASD): an open label phase 2 study (BRIGHT [ZYN2 CL 030]). Society for Developmental and Behavioral Pediatrics Annual Meeting USA2021.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an open label trial of Zyn002 in children with FXS, both the primary outcome (ADAMS) and secondary measures including the ABC demonstrated efficacy.

    “Both the primary outcome, the Anxiety Mood and Depression (ADAMS) scale and the secondary measures including the ABC, demonstrated efficacy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Heussler, 2019, A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome, J Neurodev Disord source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Functional-MRI-based evidence suggests that bumetanide reduces exaggerated amygdala activation to eye contact in individuals with ASD and contributes to increased eye-gaze time with biological stimuli and better emotional face perception.

    “There is some functional-MRI-based evidence suggesting that bumetanide reduces the exaggerated amygdala activation to eye contact in individuals with ASD and contributes to increased eye-gaze time with biological stimuli and better emotional face perception [100, 101].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [100] Hadjikhani, 2018, Bumetanide for autism: more eye contact, less amygdala activation, Sci Rep source

      Not checked in the free run.

    • cites [101] Hadjikhani, 2015, Improving emotional face perception in autism with diuretic bumetanide: a proof-of-concept behavioral and functional brain imaging pilot study, Autism source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CBD has neuromodulatory and neuroprotective effects through mechanisms including blocking neuroinflammation, potentiating anti-inflammatory pathways, improving mitochondrial function, GABAA agonist potentiation, stimulation of 5HT1A receptors, and enhancing levels of anandamide.

    “CBD has both neuromodulatory and neuroprotective effects through a number of mechanisms including blocking neuroinflammation and potentiating anti-inflammatory pathways, improving mitochondrial function, GABAA agonist potentiation, stimulation of 5HT1A receptors, and enhancing levels of anandamide (AEA) [116–119].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [116] Patricio F, Morales-Andrade AA, Patricio-Martínez A, Limón ID. Cannabidiol as a therapeutic target: Evidence of its neuroprotective and neuromodulatory function in parkinson's disease. Frontiers in Pharmacology. 2020;11. source

      Not checked in the free run.

    • cites [117] Bakas, 2017, The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors, Pharmacol Res source

      Not checked in the free run.

    • cites [118] Leweke F, Piomelli D, Pahlisch F, Muhl D, Gerth C, Hoyer C, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translational psychiatry. 2012;2(3):e94-e. source

      Not checked in the free run.

    • cites [119] Russo, 2005, Agonistic properties of cannabidiol at 5-HT1a receptors, Neurochem Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Another study suggested possible combined effects of bumetanide with ABA therapy in improving ASD symptoms on the CARS, although it was not a randomized controlled trial.

    “Another study has suggested possible combined effects of bumetanide with ABA therapy in improving ASD symptoms on the CARS, although this was not a randomized controlled trial [98].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Du, 2015, A pilot study on the combination of applied behavior analysis and bumetanide treatment for children with autism, J Child Adolesc Psychopharmacol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    FXS is a model for targeted treatments in other subtypes of ASD and treatments that work well in FXS may also be beneficial for other forms of ASD.

    “Therefore, FXS is a model for targeted treatments in other subtypes of ASD and treatments that work well in FXS may also be beneficial for other forms of ASD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Animal studies in FXS have demonstrated a hyperactive insulin receptor and up-regulation of mTORC1 and MAPK/ERK signaling pathways, as well as elevation of MMP-9 levels in the absence of FMRP.

    “Animal studies in FXS have demonstrated a hyperactive insulin receptor and up-regulation of the mammalian target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase/extracellular signal-related kinases (MAPK/ERK) signaling pathways, as well as elevation of MMP-9 levels in the absence of FMRP, the protein produced by the FMR1 gene [106–108].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [106] Gantois, 2019, Metformin for treatment of fragile X syndrome and other neurological disorders, Annu Rev Med source

      Not checked in the free run.

    • cites [107] Monyak, 2017, Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model, Mol Psychiatry source

      Not checked in the free run.

    • cites [108] Esfahanian, 2012, Effect of metformin on the proliferation, migration, and MMP-2 and-9 expression of human umbilical vein endothelial cells, Mol Med Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CBD's ability to enhance endocannabinoid levels and facilitate GABAergic transmission may improve the balance in inhibitory and excitatory transmission and help restore neuronal function and synaptic plasticity in patients with ASD and FXS even when there is no epilepsy.

    “CBD’s ability to enhance endocannabinoid levels and facilitate GABAergic transmission may serve to improve the balance in inhibitory and excitatory transmission and help restore neuronal function and synaptic plasticity in patients with ASD and FXS even when there is no epilepsy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a handful of patients with FXS treated clinically with metformin between ages 4 and 60, there was improvement in overeating and on the ABC subscales of irritability, aggression, and social avoidance.

    “In a handful of patients with FXS treated clinically with metformin between the ages of 4 and 60 years old, there was improvement in overeating but also on the ABC subscales of irritability, aggression, and social avoidance [109].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Dy, 2018, Metformin as targeted treatment in fragile X syndrome, Clin Genet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The same trial showed treatment benefits on the repetitive behavior scale, with no major adverse effects.

    “It did show treatment benefits on the repetitive behavior scale, with no major adverse effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Sprengers, 2021, Bumetanide for core symptoms of autism spectrum disorder (BAMBI): a single center, double-blinded, participant-randomized, placebo-controlled, phase-2 superiority trial, J Am Acad Child Adolesc Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A randomized controlled trial in 30 adult males with FXS demonstrated improvements with BPN14770 in behavior, the primary outcome measure (NIH toolbox), and secondary measures after only 12 weeks of treatment.

    “These studies led to patient trials of a PDE4D inhibitor called BPN14770, and an exciting study was recently published, a randomized controlled trial in 30 adult males with FXS that demonstrated improvements not only in behavior but also in the primary outcome measure, the NIH toolbox, and secondary measures after only 12 weeks of treatment [143].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Berry-Kravis, 2021, Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Mitochondrial dysfunction is associated with many forms of ASD, so medications that improve mitochondrial dysfunction are likely to be helpful for many subtypes of ASD.

    “Mitochondrial dysfunction is associated with many forms of ASD, so medications that will improve mitochondrial dysfunction are likely to be helpful for many subtypes of ASD [150].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] Frye RE, editor Mitochondrial dysfunction in autism spectrum disorder: Unique abnormalities and targeted treatments. Seminars in pediatric neurology; 2020: Elsevier. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Improvements in dendritic spine abnormalities, astrogliosis, neuroinflammation, glial activation, and downregulation of the MEK-ERK and PI3K-mTOR pathways were seen with trofinetide treatment leading to improvements in behavior and morphology of FXS.

    “Improvements in dendritic spine abnormalities, astrogliosis, neuroinflammation, glial activation, and downregulation of the MEK-ERK and PI3K-mTOR pathways were seen with trofinetide treatment leading to improvements in behavior and morphology of FXS [139].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Deacon, 2015, NNZ-2566, a novel analog of (1–3) IGF-1, as a potential therapeutic agent for fragile X syndrome, NeuroMol Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    GABA deficits are seen in many forms of ASD and medications that are agonists for the GABA system such as CBD are likely to be helpful for many subtypes of ASD.

    “For instance, GABA deficits are seen in many forms of ASD and medications that are agonists for the GABA system such as CBD are likely to be helpful for many subtypes of ASD as described above.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: GABA deficits are seen in many forms of ASD.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The current evidence-based management of ASD in children relies primarily on behavioral interventions to address the core symptoms of the condition.

    “The current evidence-based management of ASD in children relies primarily on behavioral interventions to address the core symptoms of the condition.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Anavex 2-73 has demonstrated significant benefits in the KO mouse model of FXS where multiple behaviors were improved and deficient BDNF levels were normalized.

    “It has demonstrated significant benefits in the KO mouse model of FXS where multiple behaviors were improved and deficient brain derived neurotropic factor (BDNF) levels were normalized [144].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Reyes, 2021, Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Anti-psychotic agents and stimulant medications are important in the clinical management of patients with ASD.

    “These medications including anti-psychotic agents and stimulant medications are important in the clinical management of patients with ASD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The promising mouse studies led to human trials in FXS that initially showed improvements in those with ASD plus FXS leading to phase 3 trials in FXS.

    “The promising mouse studies led to human trials in FXS [131] that initially showed improvements in those with ASD plus FXS leading to phase 3 trials in FXS [132].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [131] Berry-Kravis EM, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Science translational medicine. 2012;4(152):152ra27-ra27. source

      Not checked in the free run.

    • cites [132] Berry-Kravis, 2017, Arbaclofen in fragile X syndrome: results of phase 3 trials, J Neurodev Disord source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Arbaclofen improves three pathways: stimulation of presynaptic GABAB receptors inhibits glutamate release thereby lowering the mGluR5 pathway; stimulation of GABA receptors improves inhibition down-regulated in many forms of ASD; and arbaclofen enhances K channel activation which can also be down-regulated in many forms of ASD.

    “There are 3 pathways that are improved with arbaclofen: Stimulation of presynaptic GABAB receptors inhibits glutamate release thereby lowering the mGluR5 pathway. Stimulation of GABA receptors also improves inhibition that is down-regulated in many forms of ASD and arbaclofen also enhances K channel activation which can also be down-regulated in many forms of ASD [130].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Guglielmi, 2015, Update on the implication of potassium channels in autism: K+ channelautism spectrum disorder, Front Cell Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AV2-73 has beneficial effects in neurodegenerative disorders because of improvement in proteostasis, autophagy, oxidative stress, prevention of protein aggregates, and improvement in mitochondrial function leading to benefits in Alzheimer's disease and Parkinson's disease dementia.

    “AV2-73 also has beneficial effects in neurodegenerative disorders because of improvement in proteostasis, autophagy, oxidative stress, prevention of protein aggregates, and improvement in mitochondrial function leading to benefits in Alzheimer’ disease and Parkinson’s disease dementia [146–148].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [146] Hampel H, Williams C, Etcheto A, Goodsaid F, Parmentier F, Sallantin J, et al. A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: analysis of the blarcamesine (ANAVEX2‐73) Phase 2a clinical study. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2020;6(1):e12013. source

      Not checked in the free run.

    • cites [147] Macfarlane S, Maruff P, Cecchi M, Moore D, Zografidis T, Missling C. P1–046: New exploratory Alzheimer'sdDrug Anavex 2–73: dose dependent clinical cognitive improvement observed in mini mental state examination (MMSE) and other cognitive markers in a phase 2A study in mild-to-moderate Alzheimer's patients. Alzheimer's & Dementia. 2016;12:P419-P. source

      Not checked in the free run.

    • cites [148] Christ, 2020, The sigma-1 receptor at the crossroad of proteostasis, neurodegeneration, and autophagy, Trends Neurosci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    The role of pharmacological treatments currently is primarily to address co-morbid conditions associated with ASD and increases with age.

    “The role of pharmacological treatments currently is primarily to address co-morbid conditions associated with ASD and increases with age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Animal studies have shown that a phosphordiasterase 4DE inhibitor can rescue features of FXS in the KO mouse model and Drosophila model and can raise cAMP levels to normal.

    “Recent animal studies have shown that an inhibitor of cAMP breakdown called a phosphordiasterase 4DE inhibitor can rescue features of FXS in the KO mouse model and Drosophila model and can raise the cAMP levels to normal [141, 142].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [141] Choi, 2016, Multiple drug treatments that increase cAMP signaling restore long-term memory and aberrant signaling in fragile X syndrome models, Front Behav Neurosci source

      Not checked in the free run.

    • cites [142] Gurney, 2017, Multiple behavior phenotypes of the fragile-X syndrome mouse model respond to chronic inhibition of phosphodiesterase-4D (PDE4D), Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kaufman et al. reported significant benefits in the Rett syndrome mouse model with a rescue of behavior and BDNF levels, and this led to patient studies in Rett syndrome that have demonstrated efficacy in a controlled trial.

    “In addition, Kaufman et al. [145] also reported significant benefits in the Rett syndrome mouse model with a rescue of behavior and BDNF levels and this work lead to patient studies in Rett syndrome that have demonstrated efficacy in a controlled trial (Anavex Life Sciences press release 2021).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Kaufmann WE, Sprouse J, Rebowe N, Hanania T, Klamer D, Missling CU. ANAVEX® 2–73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome. Pharmacology Biochemistry and Behavior. 2019;187:172796. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The KO mouse was deficient in IGF1 in the brain, and this was normalized with trofinetide treatment for 28 days.

    “The KO mouse was deficient in IGF1 in the brain, and this was normalized with trofinetide treatment for 28 days.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Deacon, 2015, NNZ-2566, a novel analog of (1–3) IGF-1, as a potential therapeutic agent for fragile X syndrome, NeuroMol Med source

      Not checked in the free run.

55 of 55

  • The paper relies on this without support.

    Approximately two-thirds of autistic adolescents have been treated with psychotropic medications.

    “approximately two-thirds of autistic adolescents have been treated with psychotropic medications, especially those with challenging behaviors and co-occurring conditions like intellectual disability (ID), medical, and mental health diagnoses.”

  • The paper relies on this without support.

    Fragile X syndrome is the most common genetic disorder leading to ASD.

    “Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD.”

  • The paper relies on this without support.

    Heterogeneous etiology underlying ASD is part of the reason for a lack of efficacy in many treatment studies.

    “Part of the reason for a lack of efficacy in many treatment studies stems from the heterogeneous etiology underlying the overall term of ASD.”

  • The paper relies on this without support.

    Children with ASD tend to be more sensitive to medication effects and more likely to have adverse effects than children without ASD.

    “children with ASD tend to be more sensitive to medication effects and more likely to have adverse effects than children without ASD.”

  • The paper relies on this without support.

    Efficacy and safety of risperidone and aripiprazole have not been established for the long-term treatment of irritability in autistic individuals.

    “Given that the efficacy and safety of these medications have not been established for the long-term treatment of irritability in autistic individuals”

  • The paper relies on this without support.

    At least half of children who presented with an inadequate response or side effects to a certain medication may respond well to another one.

    “At least half of the children who presented with an inadequate response or side effects to a certain medication may respond well to another one.”

  • The paper relies on this without support.

    Most common side effects of guanfacine include sedation, constipation, irritability, and aggression.

    “The most common side effects of guanfacine include sedation, constipation, irritability, and aggression.”

  • The paper relies on this without support.

    Sleep issues are frequently reported in children with ASD potentially affecting their behavior, daily functioning, and family life.

    “Sleep issues are frequently reported in children with ASD potentially affecting their behavior, daily functioning, and family life.”

  • The paper relies on this without support.

    Principles used for psychopharmacological management are the same for children with ASD as for those with typical development.

    “The principles used for psychopharmacological management are the same for children with ASD as for those with typical development.”

  • The paper relies on this without support.

    Oxytocin is a neuropeptide synthesized in the hypothalamus that plays a critical role in social functioning.

    “Oxytocin (OXT) is a neuropeptide synthesized in the hypothalamus that plays a critical role in social functioning.”

  • The paper relies on this without support.

    Bumetanide is a loop diuretic that inhibits NKCC1 and NKCC2.

    “Bumetanide is a well-established loop diuretic that works by inhibiting sodium–potassium-chloride co-transporters, namely, NKCC1 and NKCC2.”

  • The paper relies on this without support.

    Metformin is a biguanide used for type 2 diabetes and can reduce appetite in obesity.

    “Metformin is a bi-guanide that is a primary treatment for type 2 diabetes, but it can also reduce the appetite in individuals with obesity.”

  • The paper relies on this without support.

    Lovastatin lowers cholesterol by inhibiting HMG-CoA reductase and is FDA approved for hypercholesterolemia or hyperlipidemia.

    “Lovastatin is a commonly used statin that lowers cholesterol levels, but it does this by inhibiting 3-hydroxy-3methylglutaryl coenzyme A (3HMG-CoA) reductase, and it is FDA approved for lowering hypercholesterolemia or hyperlipidemia in children and adults.”

  • The paper relies on this without support.

    Lovastatin's inhibition of HMG-CoA reductase lowers excessive protein production of the MEK-ERK pathway elevated in FXS.

    “This action lowers the excessive protein production of the MEK-ERK pathway which are elevated in FXS.”

  • The paper relies on this without support.

    The endocannabinoid system has CB1 receptors primarily in the CNS and CB2 receptors throughout the body and immune system.

    “The endocannabinoid system has two receptors CB1 found primarily in the CNS and CB2 found throughout the body and the immune system.”

  • The paper relies on this without support.

    Arbaclofen is a selective GABA-B receptor agonist and the R-enantiomer of racemic baclofen.

    “Arbaclofen, also called STX209, is a selective ɣ-aminobutyric acid type B receptor agonist that is the R-enantiomer of racemic baclofen.”

  • The paper relies on this without support.

    Anavex 2-73 is a sigma 1 receptor agonist that normalizes calcium dysregulation, oxidative stress, and mitochondrial dysfunction seen in many forms of ASD.

    “Anavex 2–73 (AV 2–73; Blarcamesine) is a sigma 1 receptor agonist that works between the endoplasmic reticulum and the mitochondrial membrane to normalize calcium dysregulation, oxidative stress, and mitochondrial dysfunction which is seen in many forms of ASD.”

  • The paper relies on this without support.

    In Angelman syndrome, the maternal copy of UBE3A is mutated or absent, and ASOs can activate the paternal copy to compensate.

    “In Angelman syndrome, where the maternal copy of UBE3A is mutated or absent, ASOs have been utilized to activate the paternal copy of UBE3A in the CNS to compensate for the missing maternal copy.”

  • The paper relies on this without support.

    Targeted treatments that reverse known neurobiological abnormalities in ASD subgroups with animal data have emerged in the last decade.

    “Targeted treatments that reverse known neurobiological abnormalities in subgroups of ASD where there is also animal data to demonstrate benefit have emerged in the last decade for subgroups of ASD.”

  • The paper relies on this without support.

    FXS is the most common single gene cause of ASD and leads the way in targeted treatments.

    “The subgroup of ASD that is leading the way in targeted treatments is FXS, the most common single gene cause of ASD.”

  • The paper relies on this without support.

    GABA deficits are seen in many forms of ASD.

    “For many subtypes of ASD, there is a GABAB deficit and arbaclofen has rescued the behavioral deficits including social deficits in the mouse models of idiopathic ASD [127], deletion of 16p11.2 [128], and FXS [129].”
    “For instance, GABA deficits are seen in many forms of ASD and medications that are agonists for the GABA system such as CBD are likely to be helpful for many subtypes of ASD as described above.”

  • The paper relies on this without support.

    No noted side effects in OXT studies on children with ASD thus far.

    “There were no noted side effects in these studies on children with ASD, thus far, although animal studies have raised the possibility of increased basal OXT levels with long-term OXT administration; the clinical effects of this being unclear.”

  • The paper relies on this without support.

    Animal studies have raised the possibility of increased basal OXT levels with long-term OXT administration.

    “There were no noted side effects in these studies on children with ASD, thus far, although animal studies have raised the possibility of increased basal OXT levels with long-term OXT administration; the clinical effects of this being unclear.”

  • The paper relies on this without support.

    Open label studies of arbaclofen in idiopathic ASD and 16p11.2 deletion showed positive behavioral benefits.

    “Both open label studies in idiopathic ASD and in those with a 16p11.2 deletion have been carried out with positive behavioral benefits.”

  • The paper relies on this without support.

    Arbaclofen has been well tolerated even at higher doses up to 15 mg tri-daily.

    “Arbaclofen has been well tolerated even at higher doses up to 15 mg tri-daily so it is likely that further studies will be carried out both in ASD and in subtypes of ASD including FXS.”

  • The paper relies on this without support.

    In a controlled trial of GTX-102 in Angelman syndrome, leg weakness occurred at higher doses leading to inability to walk in two patients.

    “However, an adverse effect of leg weakness was seen at the higher doses leading to an inability to walk in two patients.”

  • The paper relies on this without support.

    The leg weakness from GTX-102 was related to inflammation at the LP level and resolved with anti-inflammatories.

    “This was found to be related to inflammation at the level where the LP was carried out so these patients were treated with anti-inflammatories with resolution of this side effect.”
27 of 27

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Intranasal OXT holds some promise for treating social deficits, although it may only be beneficial in subsets of patients with low OXT levels.

    “intranasal OXT holds some promise [172, 173], although it may only be beneficial in subsets of patients with low OXT levels [174].”

    From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [173]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reference 72 is not an omega-3 study

    Minor

    The text cites reference 72 as a study of omega-3 fatty acids, but the reference is titled as a trial of ascorbic acid.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Hagerman Ba. Pediatric and Neurological assessments In: Hollander HaF, editor. Textbook of autism spectrum disorders 2nd edition: Am Psychiatric Assoc Publishing Washington DC; 2022. p. 87 - 100.

Cited by

Sorted by citations

Related

Authors
Aishworiya, R., Valica, T., Hagerman, R., & Restrepo, B.
Affiliations
  • National University of Singapore (SG)
  • University of California, Davis (US)
  • University of California Davis Medical Center (US)
Corresponding author
Hagerman, Randi
ORCID
Venue
Neurotherapeutics
Publisher
Elsevier BV
Published
2022-01
Volume
19
Issue
1
Pages
248-262
ISSN
1878-7479 (ISSN-L)
DOI
10.1007/s13311-022-01183-1
PMC
PMC9130393
OpenAlex
W4206549649
Semantic Scholar
023befd04f9804f08bd8e73f301740bbdd1c7ced
Cited by
233
References
149
Citations by year
2026: 36 · 2025: 71 · 2024: 74 · 2023: 40 · 2022: 12
FWCI
25.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurotherapeutics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Zynerba Pharmaceuticals
  • Azrieli Foundation
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103526)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
Keywords
autism spectrum disorder, psychopharmacological treatment, targeted therapy, metformin, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, N-acetylcysteine, atypical antipsychotics, alpha-2 adrenergic agonists, stimulant medication, comorbidities, fragile X syndrome, gene therapy, genetic etiology
MeSH terms
Autism Spectrum Disorder, Behavior Therapy, Fragile X Syndrome, Humans, Antipsychotic Agents, Comorbidity

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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