Autism Spectrum Disorder

In RCTs, purified CBD showed a reduction in seizure frequency of 30–50%; common adverse effects were somnolence, diarrhoea, vomiting and decreased appetite.

Living systematic review on cannabinoids in children; k=18 studies (n=1.285) on autism spectrum disorder identified. Most common cannabinoids: purified CBD (78,6%, n=66 studies, dose 2–50 mg/kg/day). Common adverse effects (>20% of studies): somnolence, diarrhoea, vomiting, decreased appetite. No indication-specific efficacy outcomes reported for autism.

CBD-rich cannabis showed improvements in behavioral symptoms, social responsiveness and communication, but less consistent cognitive benefits; adverse effects ranged from mild to severe.

Systematic review on CBD-rich cannabis in autism spectrum disorder; k=4 studies (2020–2024), n=353 participants from Israel, Turkey, Brazil. Improvements in behavioral symptoms, social responsiveness and communication reported; cognitive effects inconsistent. Common mild adverse effects: somnolence, decreased appetite; in individual cases increased aggression leading to treatment discontinuation.

Some studies showed improvements in various ASD symptoms (hyperactivity, sleep disturbances, anxiety, social interaction), but frequent side effects were reported; the quality of evidence remains unclear.

Systematic review on cannabis in autism spectrum disorder; k=9 studies included. Findings show reduction of hyperactivity, self-injury, sleep problems, anxiety, aggressiveness; improvement of cognition, sensory sensitivity, attention, social interaction and language. Most common adverse effects: sleep disturbances, restlessness, nervousness, appetite changes. Review calls for RCTs for definitive statements.

Some studies suggest potential efficacy, but the findings are too inconsistent between the RCTs to reliably guide clinical application.

Systematic review on CBD in neurodevelopmental disorders (incl. autism spectrum disorder); k=9 RCTs identified. Some studies show potential efficacy, but too inconsistent across all RCTs for clinical recommendation. Study characteristics, treatment properties and outcomes vary greatly; CBD suitability as a pharmacological treatment for autism remains largely undetermined.

CBD showed short-term anxiety relief, CBD+THC helped with withdrawal symptoms and sleep, but THC was associated with dose-dependent side effects and in some cases worsening of primary outcomes; no long-term effects found.

Systematic review on medical cannabis in mental disorders; k=49 controlled studies from 15 countries (18.341 screened, search October 2023/July 2024). Autism spectrum disorder included as one of 11 evaluated diagnoses. Product composition variable (THC, CBD, THC+CBD combinations); high CBD doses showed acute anxiety reduction, CBD+THC combinations improved sleep and cannabis withdrawal symptoms. THC dose-dependently associated with adverse events, in some cases worsening of primary outcomes (e.g. psychosis). No study found long-lasting medical effects. High risk of bias prevalent. Conclusion: short-term symptom relief possible, but no cure and not without risks for mental health.

Most experimental substances show insufficient evidence; some compounds (N-acetylcysteine, folinic acid, L-carnitine, coenzyme Q10, sulforaphane, metformin) show promising efficacy with a good safety profile, while leading candidates (arbaclofen, balovaptan, bumetanide) did not reach their primary endpoints.

Systematic review of experimental psychopharmacology in autism spectrum disorder (Part II); k=115 published RCTs (57 pharmacological substances, 48 nutraceuticals). For cannabidiol, insufficient evidence for efficacy and safety is stated. A small group of substances (N-acetylcysteine, folinic acid, L-carnitine, coenzyme Q10, sulforaphane, metformin) shows promising efficacy with a high safety profile.

Cannabis whole-plant extract might improve global assessment symptoms, but results for other outcomes are uncertain; very low to low evidence certainty.

Cochrane-compliant systematic review of cannabis derivatives in autism; k=11 RCTs (of which 4 with available results for children/adolescents). Five different cannabis preparations tested. One trial showed possible improvement in global symptom severity, uncertain findings for other outcomes. No quality-of-life data. Evidence certainty: very low to low (GRADE). Review concludes uncertainty about clinical efficacy.

The effect of cannabinoids on core symptoms of autism spectrum disorder is unclear; most effects were non-significant and not related to core symptoms.

Systematic review on cannabinoids for ASD core symptoms; k=5 studies (2 RCTs, 3 cohort studies) in children/adolescents. All studies reported cannabinoid effects, mostly non-significant and not related to core symptoms. Only one study found significant improvement of all three core symptoms (social interaction, communication, repetitive behaviours). Risk of bias high or very high in 4/5 studies, low in 1/5. Long-term effects unknown, safety aspects insufficiently discussed.

Responder rates for global improvement showed a benefit (49% vs 21%), but standardised outcomes were predominantly not significant; evidence remains limited.

Systematic review on cannabinoids in children/adolescents with autism; k=12 studies (4 RCTs, 8 non-RCTs), 6 ongoing trials identified. Predominantly full-spectrum extracts with CBD:THC ratio 20:1, titration up to ~10 mg/kg/day. Responder rate for global improvement vs. placebo 49% vs. 21%; improvement in social communication. No between-group differences for sleep or overall symptomatology; repetitive behaviours showed a non-significant trend. Adverse effects mostly mild (somnolence, appetite changes, sleep problems, irritability); no serious treatment-related events. GRADE certainty very low.

CBD and nabiximols show moderate to weak evidence depending on the psychiatric indication, with the strongest support for cannabis use disorder and schizophrenia.

Systematic review (k=23 studies) on CBD and nabiximols in psychiatric disorders; grade B recommendation for autism spectrum disorder (ASD) — moderate evidence for symptom relief in ASD comorbidities (including ADHD). Further large-scale RCTs required.

Limited and generally poor quality of evidence for the efficacy of cannabinoid-based products in neuropsychiatric and neurodevelopmental disorders in children and adolescents.

Systematic review on cannabinoids in neuropsychiatric/neurodevelopmental disorders in children/adolescents (≤18 years); k=5 studies specifically on autism spectrum disorder identified (out of a total of 18 included studies across 8 indications, 4466 screened). Only 1 RCT found overall, remaining 17 studies with high risk of bias (open-label, uncontrolled before-after designs, case series, case reports). Conclusion: limited and generally low-quality evidence for the efficacy of cannabis products in autism and related disorders in the pediatric population.

Disruptive behavior showed improvement (49% vs. 21% with placebo), but the primary outcome HSQ-ASD showed no difference between groups; evidence for efficacy is mixed and insufficient.

RCT n=150 (age 5–21 years) with ASD; 12 weeks whole-plant cannabis extract (CBD:THC 20:1) vs. placebo. CGI-I (co-primary endpoint): 49% vs. 21% marked/very marked improvement in disruptive behaviors (p=0.005). SRS total score (secondary): median improvement 14,9 points vs. 3,6 points placebo (p=0.009). No serious adverse events; most common adverse events somnolence (28%) and loss of appetite (25%).

CBD-rich cannabis extract significantly improved social interaction, anxiety, psychomotor agitation, meal frequency and concentration in children with autism spectrum disorder with few serious side effects.

RCT n=60 children with autism (5–11 years), CBD-rich cannabis extract vs. placebo over 12 weeks. Significant improvements: 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), meal frequency (F₁,₁₁₆=4.11, p=0.04), concentration in mild ASD (F₁,₄₈=6.75, p=0.01). Only 9,7% (3/31) of the treatment group had side effects (dizziness, insomnia, colic, weight gain).

CBD-rich cannabinoid treatment showed no superior improvement in sleep parameters compared to placebo in children with ASD.

Double-blind, placebo-controlled RCT (n=150 children/adolescents with ASD); CBD-rich cannabis extract (CBD:THC 20:1) vs. purified CBD:THC extract vs. placebo over 12 weeks; no significant benefit over placebo on sleep parameters (CSHQ); CSHQ total score improvement correlated with improvement in core symptoms (SRS, period 1: r=0,266, p=0,008; period 2: r=0,309, p=0,004).

CBD increased subcortical Glx, reduced cortical Glx; increased GABA+ in controls but reduced GABA+ in ASD, with a significant group difference in the DMPFC.

n=34 (17 ASD, 17 controls), single-dose 600 mg CBD vs. placebo; CBD increased subcortical Glx, decreased cortical Glx (both groups). Group×region interaction for GABA+: CBD increased prefrontal GABA+ in controls, decreased it in ASD (group difference significant, p-value not reported).

CBD significantly increased fALFF in the cerebellar vermis and right fusiform gyrus, primarily in the ASD group, without clear clinical behavioral effects reported.

Pharmaco-fMRI study, n=34 adult men (50% with ASD); single oral CBD administration 600 mg vs. placebo. CBD significantly increased fALFF in the cerebellar vermis and right fusiform gyrus, primarily driven by the ASD group (no significant change in controls). Within the ASD group, CBD significantly altered vermal FC with subcortical and cortical target regions.

CBDV significantly increased glutamate (Glx) in the basal ganglia of both groups, though not uniformly; in the ASD group the Glx change correlated negatively with the baseline value. No significant effects on Glx in the DMPFC or on GABA+ in either region.

n=34 (17 ASD, 17 controls), single-dose 600 mg CBDV vs. placebo; CBDV increased Glx in the basal ganglia of both groups; in ASD the Glx shift correlated negatively with baseline Glx (r not reported). No significant effect on GABA+ or prefrontal Glx.

No significant effect on the primary outcome (SRS-2), but significant improvements in secondary outcomes: reduced anxiety and improved social relating as well as lower parental stress.

n=29 autistic children (5–12 years), CBD oil with terpenes (10 mg/kg/day) vs. placebo over 2×12 weeks (crossover). Primary endpoint (SRS-2 Social Responsiveness) not significant (beta=−11,15, SE=7,19, p=0,125). Secondary improvements: DBC-2 Social Relating (beta=−2,35, p<0,05), Anxiety subscale (beta=−3,20, p=0,002), parental stress APSI (beta=−4,63, p=0,044). No differences in adaptive functioning (Vineland-3). Two children with gastrointestinal side effects.

In individuals with ASD, CBDV reduced striatal hyperconnectivity to neurotypical levels, but it is unclear whether this is associated with symptom improvement.

Pilot RCT in autism spectrum disorder (n=28, 13 ASD, 15 neurotypical), double-blind, placebo-controlled, crossover design. 600 mg cannabidivarin (CBDV) vs. placebo. CBDV reduced atypical striatal-frontal hyperconnectivity to neurotypical levels (fMRI resting-state). ASD group showed lower FC between ventral striatum and frontal/pericentral regions as well as higher intra-striatal FC vs. controls.

Significant improvements in social communication (ADOS, SRS, Vineland), but only parent-reported improvements in repetitive behaviors; no change in cognitive abilities.

Open-label study n=82 children/adolescents with ASD (of 110 recruited), 6 months CBD-rich cannabis. Significant improvements in social communication measured with ADOS, SRS and Vineland (standardized clinical assessments); greater improvements with initially more severe symptoms. Significant RRB improvements only in parent-reported SRS; no significant cognitive changes.

CBD metabolite levels were associated with improved aperiodic EEG measures and positive associations with receptive vocabulary ability, nonverbal intelligence and visuomotor coordination; overall mixed effects with some children showing improvements while others demonstrated limited changes.

n=24 boys with autism spectrum disorder and higher support needs (7-14 years), double-blind placebo-controlled, crossover; up to 20 mg/kg/day CBD over 8 weeks. CBD metabolite levels positively associated with receptive vocabulary, nonverbal intelligence and visuomotor coordination. Aperiodic EEG offset increased, aperiodic exponent (occipital) reduced. Mixed effects: some children showed improvements in cognitive/behavioral abilities, others limited changes.

About 84% of evaluable ASD patients showed moderate to significant symptom improvement after 6 months under CBD/THC oil.

Real-world analysis of n=188 ASD patients under medical cannabis (30% CBD + 1,5% THC oil) between 2015–2017. After 6 months, n=93 were evaluated: 30,1% significant improvement, 53,7% moderate improvement, 6,4% mild improvement. 25,2% reported at least one adverse event (most common: restlessness 6,6%). Cannabis well tolerated and safe in ASD.

CBD-rich cannabis improved behavioral outbursts in the majority of children, but was associated with relevant side effects including a psychotic event.

Retrospective feasibility study of CBD-rich cannabis in n=60 children with autism spectrum disorder and severe behavioral problems (age 11,8±3,5 years, 77% low-functioning). 61% showed marked or very marked improvement in behavioral outbursts (Caregiver Global Impression of Change). Most common adverse events: sleep disturbances (14%), irritability (9%), loss of appetite (9%). One psychotic event with higher THC content.

CBD group showed reduction in maladaptive behavior (internalizing) and improvement in caregivers' mental health; control group showed improvements in daily activities and socialization.

Prospective cohort study n=33 (16 CBD group with severe autism ATEC 85,5±34,00, 17 controls with moderate autism ATEC 58,6±25,53). After 3 months of CBD-rich extract: reduction in maladaptive behavior (Vineland 3 internalizing, p=0,008); caregivers showed reduction in interpersonal sensitivity (BSI p=0,038), Global Severity Index (p=0,025), Positive Symptom Distress Index (p=0,007). Control group: increase in Daily Living Activities (p=0,031) and socialization ATEC (p=0,037).

90% of patients showed improvement in at least one symptom after CBD treatment; 83,5% of all reported symptoms improved; approximately 30% improvement in irritability, social withdrawal and hyperactivity.

Prospective before-after study n=20 children with severe treatment-refractory autism, purified CBD as add-on (median 363,5 mg, range 100–700 mg), median 11 months follow-up. 90 % (18/20) showed improvement in ≥1 symptom; 83,5 % of all reported symptoms improved. Secondary outcomes: ~30 % improvement in irritability, social withdrawal, hyperactivity; repetitive behavior improved in 50 %. 65 % mild to moderate transient side effects (increased irritability, decreased appetite). 40 % reduction/discontinuation of concomitant medication.

Symptom severity scores were reduced by 73,09% from before to after cannabis use.

n=111 self-identified autistic adults, real-world tracking via Strainprint® app; symptom severity reduction of 73,09% from before to after cannabis use (Sensory Sensitivity, Repetitive Behaviors, Mental Control, Negative Affect). Higher dose associated with stronger reduction in repetitive behaviors, mental control and negative affect. No control group; subjective self-assessment.

According to parent reports, oral CBD led to improvements in comorbid ASD symptoms in the majority of children, but with variable effect on anxiety.

n=53 children with ASD (median 11 years), CBD oil 5% oral, median 66 days; self-injury/tantrums improved in 67,6%, worsened 8,8%; hyperactivity improved 68,4%; sleep problems improved 71,4%; anxiety improved 47,1%. No serious side effects; somnolence and appetite change mild.

CBD-enriched cannabis improved behavioral abnormalities, language and cognition in a portion of the children, in 19% of patients no change was reported.

n=33 children with autism spectrum disorder, CBD-enriched cannabis (mean dose 0,7 mg/kg/day, THC <3%), median 6,5 months; according to parent reports: behavioral improvement in 32,2%, language improvement in 22,5%, cognitive improvement in 12,9%, social interaction in 9,6%. No serious side effects reported under low doses.

Case report of a 15-year-old patient with autism spectrum disorder, who showed unexpectedly positive effects on behavioral symptoms, social deficits and comorbidities at a low dose of a cannabidiol-based extract; further research is considered necessary.

Single case report (n=1): 15-year-old patient with ASD, selective mutism, anxiety and controlled epilepsy. CBD-based extract at low dose led to positive effects on behavioral symptoms, core symptoms of social communication, as well as comorbid anxiety, sleep problems and weight control. Dose lower than previously reported for ASD.

CBD-enriched cannabis extract improved at least one symptom category in 14 of 15 ASD patients, most strongly seizures, ADHD, sleep and social communication.

Observational study (n=15 adherent ASD patients, of whom 10 non-epileptic); CBD-rich cannabis extract (CBD:THC 75:1) over 6–9 months; 9 of 10 non-epileptic patients showed improvement ≥30% in at least one of 8 symptom categories; 6/10 improvement ≥30% in ≥2 categories; strongest improvements in sleep disturbances, ADHD and social communication.