Autism spectrum disorder (ASD) presents with a spectrum of behavioural and developmental challenges, often complicated by comorbidities. This review evaluates multimodal interventions including pharmacological (cannabinoid therapies), nutritional (dietary and supplement-based), and behavioural (parent training programs) in treating ASD. A systematic search was conducted across PubMed and Google Scholar using keywords like “ASD,” “cannabinoids,” “dietary intervention,” and “parent training,” yielding four randomized controlled trials. Cannabinoid treatments showed improvement in behavioural outcomes, albeit with mild adverse effects.
In a double-blind trial, whole-plant cannabis extract significantly improved Clinical Global Impression-Improvement (CGI-I) scores (49% vs. 21%, p=0.005) and Social Responsiveness Scale, Second Edition (SRS-2) (median change -14.9, p=0.009) compared to placebo, though no differences were seen in Home Situations Questionnaire for Autism Spectrum Disorder (HSQ-ASD) or Autism Parenting Stress Index (APSI) scores. A multimodal dietary intervention study showed a significant increase in non-verbal IQ (+6.7 vs. -0.6, p=0.009) and improvements in Childhood Autism Rating Scale, Second Edition (CARS-2), Aberrant Behaviour Checklist (ABC), Autism Treatment Evaluation Checklist (ATEC), and biomarker profiles. Another trial using CBD-rich extract reported significant improvements in social interaction (p=0.0002), anxiety (p=0.016), and agitation (p=0.003).
These findings suggest that integrated therapeutic strategies cannabinoid-based, nutritional, and behavioural offer promising, safe options for addressing core and associated symptoms in children with ASD. This review highlights the complementary roles of these therapies and underscores the need for more inclusive and long-term studies.

Autism spectrum disorder, Cannabinoid therapy, Dietary and nutritional intervention, Parent training programs, Comorbid psychiatric disorders.

ASD is a complex neurodevelopmental condition that begins in infancy or early childhood, influenced by both genetic and non-genetic factors. The World Health Organization (WHO) characterizes ASD by impairments in social and communication skills, repetitive behaviours, atypical interests, and altered sensory perception.[1-3] The neurodiversity paradigm challenges the traditional view of autism as a disorder, instead framing it as a natural variation in brain function, emphasizing strengths rather than deficits.[4,5]

Individuals with ASD commonly experience co-occurring behavioural and psychiatric disorders, including irritability, aggression, Attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), mood disorders, suicidality, and psychosis. These comorbidities often overlap with core ASD features, complicating diagnosis. Risk factors for these co-occurring conditions include age, intellectual functioning, sex, and genetic influences.[6-8] Most research to date has focused on children and adolescents with evidence suggesting that older autistic adults have a lower risk of psychiatric comorbidity. However, autistic individuals with intellectual disabilities about one-third of the ASD population remain underrepresented in current literature.[9-11]

ASD is a genetically heterogeneous condition with a 4:1 male-to-female ratio and over 800 associated genes, as well as numerous chromosomal anomalies and syndromes. Advances in next-generation sequencing and bioinformatics have transformed genetic testing, enabling earlier diagnosis and targeted clinical interventions for neurodevelopmental disorders. These developments offer hope for new treatments, addressing conditions that were historically untreatable and affect an estimated 3% of the global population, who face significant health, financial, and emotional challenges.[12-16]

ASD is defined by challenges in social communication and restricted, repetitive behaviours, varying widely in severity across individuals. Diagnosis is possible as early as 18-24 months, when symptoms begin to differentiate from typical development.[17]

Progress in autism research has paralleled major international policy advances, driven by increased awareness, advocacy, and broader developments in human rights, mental health, and maternal and child health. Grounded in the union nation (UN) Convention on the Rights of Persons with Disabilities, this shift emphasizes dignity, inclusion, freedom of choice, and the acceptance of neurodiversity.[18]

While awareness has grown globally, service availability has not always followed. The World Health Assembly’s Mental Health Action Plan 2013-2020 (WHO, 2013b) promotes timely, culturally appropriate care, guided by principles such as universal health coverage, evidence-based approaches, and empowerment.[19]

Children with ASD often present with social communication deficits and restricted, repetitive behaviours, commonly accompanied by comorbidities such as language disorders, hyperactivity, anxiety, sensory sensitivities, challenging behaviours, and food selectivity.[20] Feeding issues in children with ASD may stem from medical conditions or sensory and behavioural factors, leading to food refusal or limited food preferences. During early childhood, mealtime experiences rooted in sensory exploration through taste, touch, and smell support social development and self-awareness.[21,22]

Family meals promote social learning around nutrition, allowing children to imitate the food choices and behaviours of family members. In infancy, feeding begins with a single food source (breast milk or formula) and expands to the family’s diet during weaning, a key developmental phase from 4 months to two years. Over time, feeding behaviour becomes influenced by social and contextual factors, such as parental practices and peer observation.[23,24]

Parent-child interactions may unintentionally reinforce food refusal or limit dietary variety, contributing to maladaptive behaviours like crying, tantrums, spitting, or self-injury during meals. Autistic children are especially prone to these behaviours due to sensory sensitivities and rigid interests. However, studies show that improving family practices can enhance dietary habits and reduce feeding difficulties.[25,26]

A comprehensive literature search was conducted in PubMed and Google Scholar for studies published between 2014 and 2024. Keywords used included “autism spectrum disorder,” “CBD,” “Cannabinoid therapy,” “Dietary interventions,” “Nutritional therapy,” and “Parent training.” The search was limited to randomized controlled trials (RCTs) and clinical trials in English.

Inclusion criteria included:

• Study population diagnosed with ASD
• Studies evaluating pharmacologic, nutritional, or behavioural interventions
• Outcome measures assessing clinical improvement

Exclusion criteria included:

• Books, commentaries, editorials, letters, documents, and book chapters
• Articles published in languages other than English
• Animal studies and in vitro (laboratory) studies
• Studies lacking a reported results section

Articles were screened by title and abstract, followed by full-text review for eligibility. Data were extracted based on study design, sample size, intervention, primary outcomes, and key findings.

Efficacy, safety, and tolerability of cannabinoid treatments in children and adolescents with ASD
In a randomized, double-blind, placebo-controlled, crossover trial at Shaare Zedek Medical Center, 150 children and adolescents (mean age 11.8 ± 4.1 years; 80% boys) with Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnosed ASD and moderate or greater behavioural problems (CGI-S ≥ 4) were enrolled between January 2017 and April 2018. Participants were randomized (1:1:1) to 12-week treatments with placebo, whole-plant cannabis extract (CBD: THC 20:1), or purified cannabinoids, followed by a 4-week washout and a second 12-week phase. Dosing started at 1 mg/kg/day CBD and 0.05 mg/kg/day THC, titrated to 420 mg/day CBD and 21 mg/day THC.

Primary outcomes were Home Situations Questionnaire (HSQ)-ASD and CGI-I. Secondary outcomes included SRS-2, Autism Parenting Stress Index (APSI), and AEs. Due to a treatment-order effect, efficacy was analysed for Period-1 only; safety data included both periods. Sample size required 43 per group; 50 were enrolled per arm. JMP version 14 was used for statistical analysis with a 2.5% alpha for co-primary outcomes. In Period-1, 49% on whole-plant extract improved on CGI-I vs 21% on placebo (p=0.005); pure cannabinoids showed a 38% response (p=0.08). SRS-2 improved with whole-plant extract (median -14.9) vs placebo (-3.6; p=0.009); not significant for pure cannabinoids (-8.2; p=0.80). No significant differences were seen in HSQ-ASD or APSI scores.

AEs were common but mostly mild or moderate. Mild AEs occurred in 89 (whole plant), 79 (pure), and 78 (placebo); moderate AEs in 44, 45, and 26, respectively. Somnolence, tiredness, and decreased appetite were more common with cannabinoids (p < 0.001 for somnolence). BMI decreased with cannabinoids (-0.36 vs +0.16; p < 0.0001). Behavioural improvement was linked to younger age, male sex, somnolence, and cannabinoid treatment, particularly whole-plant extract.

The study found no significant differences among groups in changes to HSQ-ASD total scores (primary outcome) or APSI scores (secondary outcome). However, disruptive behavior, measured by the CGI-I co-primary outcome, was much or very much improved in 49% of participants receiving the whole-plant extract (n = 45), compared to 21% in the placebo group (n = 47; p = 0.005). The median SRS total score (secondary outcome) improved by 14.9 points with whole-plant extract (n = 34), compared to 3.6 points with placebo (n = 36; p = 0.009). No treatment-related serious adverse events occurred. The most common adverse events were somnolence and decreased appetite, reported by 28% and 25% of participants on the whole-plant extract (n = 95), 23% and 21% on pure cannabinoids (n = 93), and 8% and 15% on placebo (n = 94), respectively. Interpretation of results is limited by the lack of pharmacokinetic data and variability in participant age and functional levels.[27]

Efficacy and Safety of a multimodal nutritional and dietary intervention in individuals with ASD
This one-year, single-blinded study by Adams JB et al. (ClinicalTrials.gov: NCT02059577) evaluated the long-term effects of dietary and nutritional interventions in individuals with ASD. Participants were randomized into Treatment or Non-treatment ASD groups, with a Neurotypical control group. Clinical evaluators were blinded, but participants knew their group due to the nature of diet interventions.

Participants (age between 2.5-60) were recruited in Arizona from 2011 to 2014. ASD diagnoses were confirmed via Autism Diagnostic Observation Schedule (ADOS) and/or Childhood Autism Rating Scale-Second edition (CARS-2). The Treatment group followed a stepwise protocol: vitamin/mineral supplements (Day 0), essential fatty acids (Day 30), Epsom salt baths (Day 60), carnitine (Day 90), digestive enzymes (Day 180), and a gluten-free, casein-free diet (Day 210). Baseline and Day 365 assessments included blood, urine, and clinical evaluations. Non-treatment participants maintained their regimens; neurotypical controls were assessed once.

Biomarker analyses used blinded samples processed in Clinical Laboratory Improvement Amendments (CLIA)-approved labs. Tests included complete blood count (CBC), thyroid, metabolic panels, and fatty acids. The Treatment group showed significantly greater improvement across multiple outcomes. On blinded Reynolds Intellectual Assessment Scales (RIAS) assessments, Non-Verbal IQ improved (+6.7 vs. -0.6, p=0.009). CARS-2 and SAS-Pro scores also improved (-5.5 vs. -3.2, p = 0.03; -0.93 vs. -0.33, p=0.04). Vineland Adaptive Behaviour Scale II (VABS-II) showed developmental gains (18.4 vs. 4.3 months, p=0.008).

Parent/self-reports supported these findings: Pervasive Developmental Disorders Behaviour Inventory (PDD-BI) (-35 vs. -11, p=0.0002), Autism Treatment Evaluation Checklist (ATEC) (-28% vs. -6%, p=0.00004), Aberrant Behaviour Checklist (ABC) (-26% vs. -7%, p=0.001), SRS (-14% vs. -3%, p = 0.004), Short Sensory Profile (SSP) (+12% vs. +2%, p=0.0003), and Parent Global Impressions-2 (PGI-2) (improvement in 16/17 domains, p < 0.00000001). Gastrointestinal symptoms improved (-30% vs. -10%, p=0.05). Vitamin biomarkers and CoQ10H2 improved, and homocysteine decreased (-29% vs. -7%, p=0.00002). Case reports noted resolution of pica, urinary retention, and improved endurance.

The treatment group showed a significant improvement in nonverbal intellectual ability compared to the non-treatment group, with an increase of +6.7 ± 11 IQ points versus -0.6 ± 11 IQ points (p = 0.009), as measured through blinded clinical assessment. Semi-blinded assessments revealed that the treatment group also experienced significantly greater improvements in autism symptoms and developmental age. Additionally, the treatment group demonstrated significantly higher increases in essential nutrients, including EPA, DHA, carnitine, and vitamins A, B2, B5, B6, B12, folic acid, and Coenzyme Q10.[28]

Impact of CBD-rich cannabis extract on behavioural symptoms in children with ASD
The study by Silva EAD Junior et al. was a 12-week randomized, double-blind, placebo-controlled clinical trial conducted in Brazil, adhering to CONsolidated Standards Of Reporting Trials (CONSORT) guidelines. Sample size was determined using G Power, requiring 62 participants (31 per group) for 80% power at α= 0.05. Children aged 5-11 years with an ASD diagnosis from Paraíba, Pernambuco, or Rio Grande do Norte were recruited. Exclusion criteria included comorbidities (e.g., diabetes, epilepsy) and recent cannabis use.

Caregivers provided informed consent, completed a sociodemographic form and CARS assessment. Participants received either a CBD-rich cannabis extract (0.5% concentration, 9:1 CBD: THC) or placebo, starting at 6 drops/day and titrated up to 70 drops/day. Products were identical in appearance and taste. One pharmacy student handled product distribution; other researchers were blinded. Ethical approval was granted by Universidade Federal da Paraíba (UFPB) (CAAE: 89392518.4.0000.5188), and the trial was registered (ReBEC #10743). Effectiveness was assessed through semi-structured interviews and the ATEC; safety was monitored via lab tests. Statistical analysis (R 4.0.2) used two-way analysis of variance (ANOVA), Tukey, and Wilcoxon tests at p < 0.05.

Sixty children participated (31 treatment, 29 control), with a mean age of 7.68 years; 86.67% were male. Parent demographics were similar across groups. Therapies included speech (65%), occupational (55%), and psychological (53.33%), with 55% of children on psychotropic medication. ASD severity was mild (43.33%), moderate (48.33%), or severe (8.33%).

Adverse effects were reported in 15%. Subjective improvement was noted in 67.74% of the treatment group versus 34.48% of controls. Significant improvements were seen in psychomotor agitation (p=0.00295), anxiety (p=0.0159), meals per day (p=0.045), and social interaction (p=0.000268). Mild ASD cases showed improved concentration (p=0.0124). No significant differences were found in ATEC or CARS scores. Four participants withdrew pre-trial.

The study reported significant improvements in several behavioural and functional areas for the treatment group. These included social interaction (F1,116=14.13, p=0.0002), anxiety (F1,116=5.99, p=0.016), psychomotor agitation (F1,116=9.22, p=0.003), and number of meals per day (F1,116=4.11, p=0.04). Additionally, a significant improvement in concentration was observed in children with mild ASD (F1,48=6.75, p=0.01). Regarding safety, only three children (9.7%) in the treatment group experienced adverse effects, which included dizziness, insomnia, colic, and weight gain.[29]

Clinical outcomes of a randomized trial targeting mealtime behaviours in ASD
The study by Johnson CR et al. was a parallel-group randomized trial conducted at the University of Florida and University of Rochester to assess a parent training program focused on feeding (PT-F) in children aged 2-11 years with ASD. Diagnosis was confirmed using DSM-5, and ADOS-2. Eligible participants had Brief Autism Mealtime Behaviour Inventory-Revised (BAMBI-R) scores ≥54, receptive language ≥12 months, and no confounding medical or medication issues. Medication stability for at least six weeks was required.

Participants were randomized (stratified by site, with concealed allocation) to PT-F or a waitlist control. Therapists and parents were unblinded; independent evaluators were blinded and kept separate. Feasibility was evaluated by attrition and attendance; parent satisfaction was measured via a modified parent satisfaction questionnaire (PSQ). Treatment fidelity was rated from video sessions using a checklist.

Primary child outcomes included BAMBI-R (internal consistency correlation (ICC)=0.71) and About Your Child’s Eating (AYCE) (ICC=0.86). Secondary child outcomes were CGI-I, ABC-I (ICC=0.92), and HSQ (ICC=0.88). Parent outcomes included Parenting Stress Index (PSI) (ICC=0.89), Parenting Sense of Competence (PSOC) (ICC=0.50), and caregiver strain questionnaire (CGSQ) (ICC=0.83). Safety was monitored through food records and adverse event reporting.

Between December 2014 and February 2017, 96 families were screened; 42 participants were randomized after exclusions and dropouts. The average child age was 5 years and 1 month, with most participants being male (40/42), White (83%), and non-Hispanic (81%). About 48% had IQ ≥70, and 40% were in general education.

PT-F families attended 85% of sessions, with 94% expressing satisfaction. Therapist integrity was 97%, and parent adherence 94%. Inter-rater reliability was high. The PT-F group showed significantly greater improvement than the waitlist group in BAMBI-R (p=0.003, d=0.95), AYCE (p=0.001, d=1.12), and CGI-I (48.8% responders vs. 0%, p=0.006). Improvements in ABC-I, HSQ, and parent outcomes were not statistically significant.

Among the 21 families enrolled in the PT-F program, attendance was high at 85%, with 94% of parents reporting they would recommend the program. Treatment fidelity was excellent, with therapist integrity at 97% and parent adherence at 94%. Compared to the waitlist group, children in the PT-F group showed significantly greater reductions on the two primary parent-reported measures: the BAMBI-R (T_wald=-2.79, p=0.003) and AYCE (T_wald=-3.58, p=0.001). Additionally, 48.8% of children in the PT-F group were rated as “responders” on the Clinical Global Impression-Improvement scale, compared to 0% in the waitlist group (p=0.006). While general disruptive behaviour decreased more in the PT-F group, the change was not statistically significant.[30]

Table 1: Summary of included studies

ASD presents a broad clinical spectrum characterized by core symptoms and a high prevalence of co-occurring conditions that complicate both diagnosis and treatment. While early diagnosis is possible by 18-24 months, therapeutic options remain limited and frequently inaccessible, despite global efforts toward inclusion and neurodiversity. Studies exploring both pharmacologic and non-pharmacologic interventions offer promising insights into tailored, multifaceted treatment approaches.

Cannabinoid-based treatments, as evidenced by trials from Shaare Zedek Medical Center and Silva et al., demonstrate measurable improvements in behavioural symptoms. The Israeli study found significant improvements with whole-plant extract in CGI-I and SRS-2 scores compared to placebo, although HSQ-ASD and APSI showed no significant changes. Similarly, Silva’s Brazilian trial reported improvements in psychomotor agitation, anxiety, and social interaction, particularly in mild ASD cases. However, both studies noted frequent adverse effects, including somnolence and decreased appetite, highlighting the need for careful monitoring.

Nutritional and dietary interventions also showed encouraging outcomes. The one-year study by Adams et al. reported significant improvements across cognitive, behavioural, and biochemical parameters with a multimodal nutritional protocol, supporting the integration of dietary strategies in ASD management.

Behavioural interventions, such as Johnson et al.’s parent training program targeting feeding issues, emphasized the efficacy of structured family-centered approaches. The PT-F group exhibited significant improvements in mealtime behaviour (BAMBI-R, AYCE) and clinical impressions (CGI-I), underscoring the importance of caregiver involvement and early intervention in improving quality of life. Parallel policy support and service delivery frameworks must ensure equitable access, aligning clinical advancements with the goals of inclusion and health equity for individuals with ASD.

This review consolidates evidence supporting integrative approaches in ASD management. Cannabinoid-based therapies, particularly whole-plant extracts, demonstrate behavioural improvements, albeit with notable adverse effects. Nutritional interventions enhance cognition and physiological markers, while behavioural strategies, particularly parent training, effectively address feeding and routine-related challenges. Though promising, these interventions require validation through larger and longer-term studies, particularly focusing on underrepresented subgroups such as those with intellectual disabilities. A multidisciplinary framework integrating these modalities may offer comprehensive, individualized care for ASD.

Not applicable

No funding

Corresponding Author:
Samatha Ampeti
Department of Pharmacology
Kakatiya University, University College of Pharmaceutical Sciences, Warangal, TS, India
Email: ampetisamatha9@gmail.com

Co-Authors:
Shubham Ravindra Sali, Mansi Srivastava, Raziya Begum Sheikh, Sonam Shashikala B V, Patel Nirali Kirankumar
Independent Researcher
Department of Content, medtigo India Pvt Ltd, Pune, India

All authors contributed to the conceptualization, investigation, and data curation by acquiring and critically reviewing the selected articles. They were collectively involved in the writing – original draft preparation and writing-review & editing to refine the manuscript. Additionally, all authors participated in the supervision of the work, ensuring accuracy and completeness. The final manuscript was approved by all named authors for submission to the journal.

Not applicable

None

None

https://doi.org/10.63096/medtigo3084231

Shubham RS, Samatha A,  Mansi S, Raziya BS,  Sonam SBV, Patel NK. Multimodal Therapies in ASD: Evaluating Pharmacological, Dietary, and Parent-Based Interventions. medtigo J Neurol Psychiatry. 2025;2(3):e3084231. doi:10.63096/medtigo3084231 Crossref