Efficacy and Safety of Cannabinoids for Autism Spectrum Disorder: An Updated Systematic Review

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DOI: 10.7759/cureus.80725
Efficacy and Safety of Cannabinoids for Autism
Spectrum Disorder: An Updated Systematic
Review
Danilo A. Pereira , Lidia Cheidde , Mateus Daniel R. Megiolaro , Ana Elisa F. Camargo ,
Elizabet Taylor P. Weba , Victor G. Soares , Anderson M. Pereira da Silva , Laura Cheidde ,
Pedro Paulo Ladeira Júnior , Dillan C. Amaral , Rafael Triaca , Matheus Augusto N. Fernandes ,
Paula Maria P. Mimura
1. Department of Human Reproduction and Childhood, Pontifícia Universidade Católica de São Paulo, Sorocaba, BRA 2.
Faculty of Medicine, Pontifícia Universidade Católica de São Paulo, Sorocaba, BRA 3. Faculty of Medicine, Universidade
Estadual da Região Tocantina do Maranhão, Imperatriz, BRA 4. Faculty of Medicine, Universidade Federal dos Vales do
Jequitinhonha e Mucuri, Diamantina, BRA 5. Department of Pharmacology, Universidade Federal do Vale do São
Francisco, Petrolina, BRA 6. Department of Orthopaedics and Trauma, Universidade Cidade de São Paulo (UNICID), São
Paulo, BRA 7. Faculty of Medicine, Universidade Cidade de São Paulo (UNICID), São Paulo, BRA 8. Faculty of Medicine,
Universidade Federal do Rio de Janeiro, Rio de Janeiro, BRA 9. Faculty of Medicine, Universidade Unigranrio Escola de
Ciências da Saúde, Duque de Caxias, BRA 10. Faculty of Medicine, Universidade Anhembi Morumbi, São José dos
Campos, BRA 11. Department of Specialized Rehabilitation, Hospital Estadual Especializado em Reabilitação "Dr.
Francisco Ribeiro Arantes", Itu, BRA
Corresponding author: Lidia Cheidde, lidiacheidde@gmail.com
Abstract
Autism Spectrum Disorder (ASD) lacks an established pharmacological treatment protocol, prompting
interest in alternative therapeutic approaches, such as cannabidiol (CBD). This systematic review evaluates
the potential efficacy and safety of CBD-rich formulations in managing ASD symptoms. A comprehensive
search of PubMed, Embase, Scopus, Web of Science, and the Cochrane Library identified seven studies
encompassing 494 patients from Brazil and Israel. Preliminary findings suggest that CBD-rich formulations
may provide modest benefits for sleep and social interaction, with a reduction in anxiety symptoms.
Regarding core ASD symptoms and behavioral outcomes, cannabinoids demonstrated greater efficacy
compared to placebo in some studies. However, adverse events varied, and response to treatment was
inconsistent across individuals. While cannabinoids, particularly CBD-rich formulations, appear to be
relatively safe and potentially beneficial, further large-scale, controlled trials comparing CBD to established
ASD treatments are essential to clarify its role and long-term impact in ASD management.
Categories: Neurology, Pharmacology, Therapeutics
Keywords: a systematic review, autism spectrum disorder, cannabinoids, efficacy, safety
Introduction And Background
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by difficulties in
social communication and restricted, repetitive behaviors [1]. It affects about 1%-2% of children worldwide,
with recent estimates in the United States indicating that approximately 1 in 36 children is diagnosed with
ASD [2]. Despite the growing prevalence of ASD, there are currently no established pharmacological
treatments for its core symptoms [3]. Clinicians often manage associated behaviors (such as irritability,
hyperactivity, or anxiety) with medications like antipsychotics or antidepressants, but these provide limited
benefit and can cause significant side effects (e.g., weight gain and sedation) [3]. This therapeutic gap has
led families and clinicians to seek alternative interventions, including cannabinoid-based therapies.
Cannabinoids have emerged as a potential therapeutic option due to their interaction with the
endocannabinoid system (ECS), which regulates brain function, mood, and immune responses. The primary
receptors, CB1 and CB2, are involved in neurotransmitter modulation and neuroinflammation, both of
which are implicated in ASD [4,5]. Studies have reported lower endocannabinoid levels in children with ASD,
suggesting that ECS dysfunction may contribute to symptoms [6,7]. Additionally, cannabidiol (CBD)
interacts with serotonin (5-HT1A) and PPAR receptors, which may underlie its potential anxiolytic and
neuroprotective effects [7-9].
Previous research on cannabinoids in ASD highlights both a potential therapeutic signal and notable gaps in
knowledge. Early studies suggest that cannabinoids (particularly CBD-enriched preparations) may help
reduce irritability, aggression, anxiety, and other behavioral problems in some individuals with ASD and
generally appear to be well tolerated. The mechanistic rationale - involving the ECS and related pathways -
provides a compelling reason to explore this treatment, yet it also underscores the complexity of how
cannabinoids might interact with neurodevelopmental processes.
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Open Access Review Article
How to cite this article
Pereira D A, Cheidde L, Megiolaro M R, et al. (March 17, 2025) Efficacy and Safety of Cannabinoids for Autism Spectrum Disorder: An Updated
Systematic Review. Cureus 17(3): e80725. DOI 10.7759/cureus.80725

Given the increasing use of cannabinoids by ASD patients and the limited high-quality evidence, this
systematic review updates the literature, aiming to evaluate the efficacy and safety of cannabinoids in ASD
[10,11].
Review
Methods
Protocol
This systematic review was performed following the handbook of the Cochrane Collaboration [12] and the
Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines [13].
Search Strategy and Data Source
We systematically searched PubMed, Embase, Web of Science, Scopus, and Cochrane databases. Our search
was last updated on January 28th, 2025. The complete search strategy is: ("Autism Spectrum Disorder" OR
"ASD") AND ("Cannabinoids" OR Cannabidiol OR "CBD" OR "THC" OR "Tetrahydrocannabinol"). All records
retrieved were independently assessed by three authors (L.C., M.D.R.M., and D.C.A.). Full texts arbitrated a
decision regarding full-text retrieval were reviewed by L.C. and M.D.R.M., and discussed regarding inclusion
and exclusion criteria.
The articles were uploaded to the Rayyan platform (Qatar Computing Research Institute, Ar-Rayyan, Qatar)
for title and abstract reading. The first selection was focused on the title and abstract, with no limitations on
the publication date. In this stage, all duplicated titles were removed, and articles that did not directly
address the subject of interest were excluded. Two reviewers (L.C. and M.D.R.M.) performed this step
independently; doubts were clarified with the aid of a third researcher (D.C.A.). Full texts were reviewed by
L.C. and M.D.R.M. and discussed regarding inclusion and exclusion criteria. Full texts of potential articles
were read in their entirety. Reference lists of eligible studies and relevant reviews were searched for
additional articles.
Eligibility Criteria - Inclusion and Exclusion Criteria
We included randomized clinical trials (RCTs) and observational studies that investigated the use of
cannabinoids in patients with ASD, with reports of at least one outcome of interest. Studies were excluded if
they did not assess any relevant efficacy or safety outcomes, were not published in English, involved animal
or in vivo models, or were classified as reviews, case reports, abstracts, protocols, letters, or comments.
Data Extraction and Outcomes Assessment
The following data were extracted from the selected articles: authors, year of publication, study location,
type of study, sample size and age, patient characteristics, duration of intervention, therapeutic scheme,
follow-up time, and main results. Two reviewers (E.T.P.W. and P.P.L.J.) were responsible for extracting and
managing the data independently, which were inserted into an EXCEL® spreadsheet (Microsoft® Corp.,
Redmond, WA, USA). Doubts were clarified with the help of the third researcher (L.C.).
The included studies assessed various clinical outcomes related to the efficacy and safety of cannabinoids in
patients with ASD. The primary outcomes analyzed were sleep quality, core autism symptoms, behavior,
social effects, anxiety, and adverse events. No specific measurement scales were excluded, ensuring a
comprehensive assessment of these clinical parameters.
Risk of Bias Assessment
We evaluated the risk of bias using version 2 of the Cochrane Risk of Bias assessment tool [12] and the
updated version of the Cochrane Risk of Bias in Non-randomized Studies of Interventions tool (ROBINS-I)
[13]. Two authors independently assessed the studies for quality assessment (E.T.P.W. and V.G.S.), and any
conflict was resolved by a third author (L.C.).
Results
Study Selection and Characteristics
A total of 1,509 studies were identified: 139 from PubMed, 147 from Web of Science, 915 from Embase, 247
from Scopus, and 34 from Cochrane. After the removal of duplicates, 987 studies remained for the title and
abstract screening. Subsequently, 13 articles underwent a full-text review, and six were excluded due to
incompatibility with the eligibility criteria. Therefore, seven studies were included [3,14-19]. The study
selection process is illustrated in Figure 1.
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FIGURE 1: PRISMA Flow Diagram
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis
Seven studies were included in this review, involving 494 patients from Israel and Brazil. The mean age of
participants ranged from 7.68 to 12.9 years. The proportion of male participants was high (n = 366, or
74.01%). Autism severity was mostly classified as severe or was not reported. Concomitant medications
included antipsychotics, mood stabilizers, stimulants, and benzodiazepines. It should be noted that the Aran
et al. [3] and Schnapp et al. [15] studies are part of the same clinical trial and, therefore, have the same
intervention protocols for the same patients (Table 1).
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Author
(Year) Country Study
Design
Total
Patients
Mean
Age
± SD
Male/Female Autism
Severity Concomitant Medications (No. of Patients)
Junior et al.
(2024) [14] Brazil Randomized
Clinical Trial 60
7.68
±
1.74
52/8
Mild (n =
26),
Moderate (n
= 29),
Severe (n =
5)
Non-specified (n = 28)
Aran et al.
(2019) [19] Israel Retrospective
Cohort Study 60 11.8
± 3.5 50/10 Severe
(CGI-S: 6/7)
Antipsychotics (n = 43), Mood stabilizers (n =
10), Benzodiazepines (n = 7), SSRI (n = 4),
Stimulants (n = 4)
Aran et al.
(2021) [3] Israel Randomized
Clinical Trial 150 11.8
± 4.1 120/30 Severe
Antipsychotics (n = 18), Anticonvulsants (n =
10), Benzodiazepines (n = 5), SSRI (n = 21),
Stimulants (n = 20), Melatonin (n = 12)
Schnapp et
al. (2022)
[15]
Israel Randomized
Clinical Trial 150 11.8
± 4.1 120/30 Severe
Antipsychotics (n = 18), Anticonvulsants (n =
10), Benzodiazepines (n = 5), SSRI (n = 21),
Stimulants (n = 20), Melatonin (n = 12)
Barchel et al.
(2019) [18] Israel Prospective
Cohort Study 54
11.3
±
3.96
45/8 NR
Stimulants (n = 5), Antipsychotics (n = 37),
Anti-epileptics (n = 8), Melatonin (n = 4),
Antidepressants (n = 2), Other anti-
muscarinics (n = 3), Alpha agonist (n = 1)
Hacohen et
al. (2022)
[16]
Israel Prospective
Cohort Study 82 9.3 ±
0.5 44/38 NR NR
Bar-Lev
Schleider et
al. (2019)
[17]
Israel Retrospective
Cohort Study 188 12.9
± 7.0 154/34 NR
Antipsychotics (n = 55), Anti-epileptics (n =
46), Antidepressants (n = 10), Hypnotics and
sedatives (n = 10), Anxiolytics (n=7)
TABLE 1: Baseline Characteristics
Note: Aran et al. [3] and Schnapp et al. [15] analyze the same population and intervention but assess different outcomes, which justifies including both.
However, their patients were counted only once.
CGI-S: Clinical Global Impression Scale-Severity; SSRI: Selective Serotonin Reuptake Inhibitor; NR: Not Reported
Intervention Description
Table 2 summarizes the intervention types, dosing schedules, and concentration details, highlighting the
differences and methodologies employed across the studies.
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Author
(Year) Intervention Description Posology Route
Administration
Follow-
Up
Junior et
al. (2024)
[14]
31 CBD-rich cannabis extract (ratio of
9CBD:1THC)/29 Control (placebo)
from ABRACE
Starting dose: 3 drops every 12 hours, titrated by 2
drops every 12 hours twice a week, up to max 70
drops/day
Orally 12
weeks
Aran et al.
(2021) [3]
50 whole-plant cannabis extract (ratio
of 20CDB:1THC) (BOL-DP-O-01-W,
BOL Pharma, Israel)/50 Purified
CBD/THC extract (ratio of
20CDB:1THC) (BOL-DP-O-01-W, BOL
Pharma, Israel)/50 Control (placebo)**
Starting dose: 1 mg/kg/day CBD + 0.05 mg/kg/day
THC, increased by 1 mg/kg/day CBD + 0.05 mg/kg/day
THC every other day. Maximum dose: 10 mg/kg/day
CBD + 0.5 mg/kg/day THC (max 420 mg CBD, 21 mg
THC/day) for children 20-40 kg; 7.5 mg/kg/day CBD +
0.375 mg/kg/day THC for children >40 kg.
Orally
(sublingual
whenever
possible)
12
weeks
Schnapp et
al. (2022)
[15]
50 whole-plant cannabis extract (ratio
of 20CDB:1THC) (BOL-DP-O-01-W,
BOL Pharma, Israel)/50 Purified
CBD/THC extract (ratio of
20CDB:1THC) (BOL-DP-O-01-W, BOL
Pharma, Israel)/50 Control (placebo)**
Starting dose: 1 mg/kg/day CBD + 0.05 mg/kg/day
THC, increased by 1 mg/kg/day CBD + 0.05 mg/kg/day
THC every other day. Maximum dose: 10 mg/kg/day
CBD + 0.5 mg/kg/day THC (max 420 mg CBD, 21 mg
THC/day) for children 20-40 kg; 7.5 mg/kg/day CBD +
0.375 mg/kg/day THC for children >40 kg.
Orally
(sublingual
whenever
possible)
12
weeks
Aran et al.
(2019) [19]
60 whole-plant cannabis extract (ratio
of 20CBD:1THC) from multiple
suppliers (CHP, Tikun Olam, BOL
Pharma)
Starting dose: 1 mg/kg/day of CBD, two to three times
per day. Maximum dose: 10 mg/kg/day of CBD two to
three times per day.***
Sublingually
10.9 ±
2.3
months
Bar-Lev
Schleider
et al.
(2019) [17]
188 cannabis oil solution (30% CDB
and 1.5% THC, ratio of 20CBD:1THC)
Starting dose: 1 drop (0.05 mL) three times a day
(each drop contains 15 mg CBD and 0.75 mg THC).
Titration was individualized based on patient response.
Max dose: up to 20 drops three times a day.
Sublingually 6
months
Hacohen et
al. (2022)
[16]
110 whole-plant cannabis extract (ratio
of 20CDB:1THC) (Nitzan Spectrum®,
Search Medical Group, Israel)
Starting dose: 1 drop daily (each drop contains 0.3 mg
THC and 5.7 mg CBD), gradually increased until
improvements were noted. Maximum dose: 10
mg/kg/day CBD (max 400 mg/day) and 0.5 mg/kg/day
THC (max 20 mg/day).
Orally 6
months
Barchel et
al. (2019)
[18]
53 cannabinoid oil solution (30% CBD,
20:1 CBD:THC ratio) from Tikun Olam
Starting dose: Individualized titration, recommended
daily dose to 16 mg/kg/day CBD (max 600 mg/day)
and 0.8 mg/kg/day THC (max 40 mg/day)
Oral (sublingual
drops)
10.15 ±
5.29
months
TABLE 2: Intervention and Posology Description
**Aran et al. [3] and Schnapp et al. [15] analyze the same population and intervention, but assess different outcomes, w hich justifies including both.
However, their patients were counted only once; ***No other details were provided.
CBD: Cannabidiol; THC: Tetrahydrocannabinol; CBD:THC: Cannabidiol to Tetrahydrocannabinol Ratio
Anxiety
RCT studies: In the Junior et al. [14] study, anxiety levels were assessed using a non-specific semi-structured
questionnaire. The CBD-rich cannabis group showed a significant reduction in anxiety, with a mean score of
1.84 (±1.39) compared to 2.90 (±1.23) in the placebo group (p = 0.0159).
In contrast, Aran et al. [3] and Schnapp et al. [15] are part of the same RCT but analyzed different outcomes.
Schnapp et al. [15] focused on sleep-related anxiety using the Children’s Sleep Habit Questionnaire (CSHQ)
and found no significant difference (p = 0.59) in anxiety scores between the CBD and placebo groups (CBD =
-0.4 ± 1.2; placebo = -0.6 ± 1.3). Additionally, Aran et al. [3] reported anxiety-related adverse events across
treatment groups. In the whole-plant extract group, 20% (10 out of 50) of participants experienced adverse
anxiety-related effects, while in the pure cannabinoids group, 27% (14 out of 50) were affected. In contrast,
14% (7 out of 50) of participants in the placebo group also reported anxiety-related adverse events.
Observational studies: Among observational studies, Barchel et al. [18] used a parent-reported symptom
questionnaire and found that, among 17 participants, 47.1% (8 out of 17) showed improvement, while 29.4%
(5 out of 17) had no change, and 23.5% (4 out of 17) experienced worsening. Similarly, Bar-Lev Schleider et
2025 Pereira et al. Cureus 17(3): e80725. DOI 10.7759/cureus.80725 5 of 12

al. [17] used a parent-reported treatment effectiveness scale and found that, among 27 patients receiving
cannabinoid oil, 88.8% (24 out of 27) showed improvement, while 11.1% (3 out of 27) had no change or
worsening. Hacohen et al. [16] used the Autism Diagnostic Observation Schedule (ADOS-2) and reported
that anxiety was indirectly affected, with larger social communication improvements noted in those with
more severe initial symptoms. However, this study did not directly measure anxiety as an independent
outcome.
Sleep
RCT studies: In the Junior et al. [14] study, sleep quality was assessed using a non-specific semi-structured
questionnaire. The CBD-rich cannabis group showed an improvement in sleep scores, with a mean change of
0.77 (±1.61) in the cannabis group, compared to 0.28 (±0.59) in the placebo group (p = 0.0711), though the
result did not reach statistical significance. Meanwhile, Aran et al. [3] and Schnapp et al. [15] are from the
same RCT, analyzing different aspects of sleep disturbances using the CSHQ. Schnapp et al. [15] found no
significant improvement in sleep parameters with cannabinoids compared to placebo. For total sleep scores,
the mean change was -2.9 (±9.2) in the pure cannabinoids group, -2.3 (±5.6) in the whole-plant extract
group, and -1.4 (±6.6) in the placebo group (p = 0.63), indicating no statistical difference.
Observational studies: In Barchel et al. [18], a parent-reported questionnaire revealed that, among 21
participants with reported sleep issues, 71.4% (15 out of 21) showed improvement, while 23.8% (5 out of 21)
had no change, and 4.7% (1 out of 21) experienced worsening. Similarly, Bar-Lev Schleider et al. [17] used a
parent-reported treatment effectiveness scale and found that, among 27 patients using cannabinoid oil,
88.8% (24 out of 27) showed improvement in sleep, while 11.1% (3 out of 27) had no change or worsening.
Hacohen et al. [16] did not directly measure sleep outcomes but reported that parents noted general
behavioral improvements, including sleep disturbances, among children with more severe baseline
symptoms. However, without direct sleep assessments, it remains unclear if cannabinoids specifically
influenced sleep or if improvements were secondary to other behavioral changes. The Aran et al. [19] study
reported caregiver-perceived improvements in sleep as part of a broader clinical evaluation but did not
provide specific quantitative sleep measures.
Autistic Core Symptoms
RCT studies: In the Junior et al. [14] study, autistic core symptoms were assessed using the Autism
Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS). The ATEC total score
at the final assessment was 64.84 (±26.82) in the CBD-rich cannabis group and 75.00 (±32.89) in the placebo
group, with the difference not being statistically significant (p = 0.098). Similarly, the CARS final score was
33.47 (±8.48) in the cannabis group and 37.83 (±9.02) in the placebo group, with the difference also not being
statistically significant (p = 0.188). The Aran et al. [3] and Schnapp et al. [15] studies originate from the same
RCT, analyzing autistic core symptoms using the Autism Parenting Stress Index (APSI). In the Aran et al. [3]
trial, whole-plant cannabis treatment resulted in a change from a baseline of -6.73 (±11.58) in APSI scores,
while the pure cannabinoid group had no reported baseline scores. The placebo group showed a smaller APSI
change of -1.76 (±10.25), suggesting greater improvement in the whole-plant cannabis group; however, the
p-value was not significant in comparison with whole-plant and pure cannabis versus placebo (p = 0.502 and
p = 0.513).
Observational studies: Aran et al. [19] reported that whole-plant cannabis reduced APSI scores from 2.04
(±0.77) at baseline to 1.37 (±0.59) at follow-up, indicating an improvement of 0.66 ± 0.74 in autism-related
parental stress. In Hacohen et al. [16], autistic symptoms were evaluated using ADOS-2. The ADOS-2 total
score showed a mean change of -0.56 (±0.17) from baseline in the CBD-rich cannabis group, while baseline
values and placebo group scores were not reported. The Social Responsiveness Scale (SRS-2) total score
improved by -3.29 (±1.13), and the Vineland Adaptive Behavior Scale (Vineland-3) total score increased by
+4.37 (±1.18), indicating mild improvements in adaptive behavior. In Barchel et al. [18], a parent-reported
questionnaire found that 74.5% of children showed improvement in autistic symptoms, while 21.6% had no
change, and 3.9% experienced worsening. Similarly, Bar-Lev Schleider et al. [17] used a parent-reported
effectiveness scale and found that 91.4% (of an unspecified number of participants) reported improvements,
while 8.6% saw no change.
Social Effects
RCT studies: In the Junior et al. [14] study, social interaction was measured using an unspecified scale. The
CBD-rich cannabis group had a final score of 1.68 (±1.01), while the placebo group scored 2.83 (±1.10),
indicating better social outcomes in the cannabis group (p < 0.05). The ATEC Socialization subscale showed
similar trends, with the CBD-rich cannabis group scoring 13.64 (±6.31) compared to 17.83 (±9.83) in the
placebo group; however, the p-value was 0.113.
The Aran et al. [3] and Schnapp et al. [15] studies originate from the same RCT, analyzing social effects using
the SRS-2. Aran et al. [3] reported that the whole-extract cannabis group showed a mean change from
baseline of -14.9 (±14.34), the pure cannabinoid group showed a mean change from baseline of -9.13
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(±28.33), while the placebo group improved by -5.85 (±23.17) in SRS-2 scores, suggesting a significant
benefit of whole-extract (p = 0.009) and a moderate but non-significant benefit of pure cannabinoids versus
placebo (p = 0.801).
Observational studies: In Hacohen et al. [16], in the CBD-rich cannabis group, social symptoms were
evaluated using the ADOS-2 Social Affect Score, which improved by -0.49 (±0.18) from baseline, and the SRS-
2 Social Score, which improved by 2.51 (±1.19). These findings suggest a possible positive impact of
cannabinoids on social responsiveness, though placebo data were not provided for direct comparison. In
Barchel et al. [18], a parent-reported questionnaire showed that 71.4% of children displayed improvement in
social interaction, while 23.8% showed no change, and 4.7% experienced worsening. Similarly, Bar-Lev
Schleider et al. [17] used a parent-reported effectiveness scale but did not provide numerical data on social
improvements.
Behavioral Outcomes
RCT studies: In the Junior et al. [14] study, behavior was assessed using multiple measures. The ATEC Health
and Behavior subscale showed a final score of 25.35 (±10.79) in the CBD-rich cannabis group and 27.17
(±11.03) in the placebo group (p = 0.119). Similarly, psychomotor agitation scores were lower in the cannabis
group (1.64 ± 1.28) compared to placebo (2.65 ± 1.14) (p = 0.00295), and stereotypy scores were also reduced
in the cannabis group (1.45 ± 1.06) versus placebo (2.07 ± 1.03) (p = 0.3853), suggesting a potential benefit of
cannabinoids in reducing repetitive and hyperactive behaviors. However, only the psychomotor agitation
was statistically significant. The Aran et al. [3] and Schnapp et al. [15] studies originate from the same RCT,
analyzing behavioral effects using the Clinical Global Impression-Improvement (CGI-I) scale. Aran et al. [3]
found that 49% of participants in the whole-plant cannabis group and 38% in the pure cannabinoid group
were rated as “much improved” or “very much improved,” compared to 21% in the placebo group (p = 0.005).
However, changes in Home Situation Questionnaire-ASD (HSQ-ASD) scores did not differ significantly
between groups (p > 0.05), suggesting that caregiver-reported disruptive behaviors did not improve
consistently.
Observational studies: In Aran et al. [19], 61% of participants using whole-plant cannabis were rated as
improved in behavior problems on the Caregiver Global Impression of Change (CGIC) scale. Similarly,
Barchel et al. [18] reported that parents observed improvements in aggression and behavioral regulation,
though specific numerical data were not provided. In Hacohen et al. [16], behavior was evaluated using the
SRS-2 Restricted and Repetitive Behavior (RRB) score, which showed a mean improvement of -2.88 (±1.14)
in the CBD-rich cannabis group. Finally, Bar-Lev Schleider et al. [17] did not provide specific quantitative
data on behavioral outcomes.
Adverse Events
In the studies that included a comparison between the intervention and placebo, the number of adverse
events was very similar between the control and intervention groups, indicating the safety of the
intervention. In the Junior et al. [14] and Schnapp et al. [15] studies, the adverse effects were not specified
individually; only the total number of events, over the total number of patients, was provided. Table 3
reports the summary of adverse events.
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Study
(Year) CBD (Number of Events) Control (Number of
Events)
Treatment
Duration
Aran et al.
(2021) [3]
Somnolence: 51, Decreased appetite: 46, Weight loss: 25, Tiredness: 59, Euphoria:
39, Anxiety: 47
Somnolence: 7,
Decreased appetite: 14,
Weight loss: 4,
Tiredness: 19,
Euphoria: 13, Anxiety:
14
3 months
Junior et
al. (2024)
[14]
Dizziness, insomnia, colic, and weight gain: 4 Dizziness, insomnia,
colic, and weight gain: 5 6 months
Schnapp et
al. (2022)
[15]
**Non-specified AE: 2 **Non-specified AE: 1 3 months
Aran et al.
(2019) [19]
Total: 29, Sleep disturbances: 8, Restlessness: 5, Nervousness: 5, Loss of appetite:
5, Gastrointestinal symptoms: 4, Unexplained laugh: 4, Mood changes: 3, Fatigue: 3,
Nocturnal enuresis: 2, Gain of appetite: 2, Weight loss: 2, Weight gain: 2, Dry mouth:
2, Tremor: 2, Sleepiness: 1, Anxiety: 1, Confusion: 1, Cough: 1, **Psychotic event: 1
NR
Mean ±
SD: 10.9 ±
2.3
months
Barchel et
al. (2019)
[18]
Somnolence: 12, Appetite decrease: 6, Appetite increase: 4, Insomnia: 2, Sense
abnormality response (to temperature): 2, Eyes blinking: 2, Diarrhea: 2, Hair loss: 1,
Nausea: 1, Confusion: 1, Acne: 1, Palpitations: 1, Urinary incontinence: 1, Eye
redness: 1, Constipation: 1
NR
Median
(range):
66 (31-588
days)
Hacohen et
al. (2022)
[16]
**5 Increased aggression, **3 Anxiety, **1 Weight gain, **1 Abdominal pain, **1
Hyperactivity, **1 Decrease in communication NR 6 months
Bar-Lev
Schleider
et al.
(2019) [17]
Restlessness: 6, Sleepiness: 3, Psychoactive effect: 3, Increased appetite: 3,
Digestion problems: 3, Dry mouth: 2, Lack of appetite: 2, **5 Stopped treatment due
to non-specified AE
NR 6 months
TABLE 3: Summary of Adverse Events
**Drop-out participants
Note: Aran et al. [3] and Schnapp et al. [15] adopt a two-phase crossover approach, which justifies the doubling of the total number of events in relation to
the study population.
NR: Not Reported; CBD: Cannabidiol
Risk of Bias Assessment
The risk of bias assessment revealed varying levels of bias across the included studies. Among the RCTs
(assessed using RoB 2), Junior et al. [14] had an overall "some concerns" rating due to deviations from
intended interventions and selection of reported results, while Aran et al. [3] and Schnapp et al. [15] had a
"high" risk of bias, mainly due to concerns in randomization and measurement of outcomes (Figure 2). For
the non-randomized studies (assessed with ROBINS-I), Barchel et al. [18] and Hacohen et al. [16] showed a
moderate risk of bias, particularly in confounding and deviations from intended interventions (Figure 3). In
contrast, Aran et al. [19] and Bar-Lev Schleider et al. [17] had a serious risk of bias, primarily due to
confounding, selection of reported results, and measurement of outcomes, highlighting potential
limitations in the reliability of their findings.
2025 Pereira et al. Cureus 17(3): e80725. DOI 10.7759/cureus.80725 8 of 12

FIGURE 2: RoB-2
RoB-2: Risk of Bias-2
FIGURE 3: ROBINS-I
ROBINS-I: Risk of Bias in Non-randomized Studies of Interventions tool
Discussion
This systematic review explored the efficacy and safety of cannabinoids, alone or compared to placebo, in
managing autism symptoms in children and adolescents. Our analysis incorporated data from seven studies,
including 494 patients, and focused on key clinical outcomes, such as sleep, autistic core symptoms, anxiety,
behavior, social effects, and adverse events.
Preliminary evidence suggests that CBD-rich formulations may hold promise for managing certain ASD
symptoms. Improvements were noted in anxiety, sleep quality, social effects, and behavior, although these
findings varied across studies. Importantly, adverse events were generally mild and occurred at similar rates
in cannabinoid and placebo groups, supporting the intervention’s safety profile.
Regarding sleep, studies indicate a slight improvement in sleep quality, reflected in better well-being scores
(e.g., CSHQ) [16]. These findings align with recent literature emphasizing CBD’s potential role in sleep
regulation [18]. Additionally, autistic core symptoms showed positive responses, with improvements in
scores such as SRS-2, ATEC, and CARS, suggesting enhanced behavior and social interaction [19]. Some
studies also reported reductions in hyperactivity, agitation, self-injurious behavior, and epilepsy, along with
improvements in communication skills, attention, and eye contact [20-22].
Anxiety reduction was another notable finding, with results from Junior et al. [14] and Schnapp et al. [15]
corroborating broader evidence of cannabinoids' anxiolytic effects. Some studies also explored the use of
CBD-enriched formulations in ASD patients with ADHD, showing promising outcomes [23,24]. While a range
of side effects was reported, somnolence was the most frequently observed, consistent with existing
literature [24].
2025 Pereira et al. Cureus 17(3): e80725. DOI 10.7759/cureus.80725 9 of 12

Research on cannabinoids' effects on core autism symptoms - such as social communication deficits and
repetitive behaviors - has yielded mixed results [25]. Some studies suggest potential improvements in these
areas, while others find limited impact. For instance, a systematic review highlighted that changes in core
symptoms were scarcely explored, with only one study reporting some improvements in communication and
social interaction in a small sample of Brazilian children with ASD [25]. While some studies reported
improvements in SRS-2, ATEC, and CARS scores, suggesting enhanced social interaction and behavior,
others found no significant differences when compared to placebo [16,19]. These results align with previous
research indicating that cannabinoids may have a mild effect on core ASD symptoms but are not a definitive
treatment [25]. The mechanisms behind these potential benefits could be linked to CBD’s interaction with
the ECS, which plays a role in neurodevelopment and social behavior [25,26].
The safety profile of cannabinoid treatments in ASD populations has been generally favorable, with most
adverse events reported as mild to moderate. Common side effects include drowsiness, decreased appetite,
weight loss, anxiety, and restlessness. Despite these occurrences, cannabinoids are often considered well-
tolerated compared to traditional pharmacological interventions. Nonetheless, careful monitoring and
individualized dosing are essential to minimize potential risks, and further research is necessary to fully
elucidate the long-term safety of cannabinoid use in ASD treatment [26,27].
Mechanistically, CBD interacts with the ECS, a critical signaling network involved in neurodevelopment,
social behavior, and homeostasis. Emerging evidence also suggests its role in gut-brain communication,
further linking it to ASD pathophysiology [25,26]. Preclinical research, such as the study by Poleg et al.,
demonstrated reductions in repetitive behaviors and anxiety-related symptoms in ASD mouse models
following CBD treatment [8]. Additionally, low doses of THC in specific formulations appear beneficial for
social behaviors, though their long-term effects remain uncertain. These findings support the potential of
personalized cannabinoid therapies tailored to ASD subtypes.
Several meta-analyses have examined cannabinoids in conditions like epilepsy and multiple sclerosis, but
systematic reviews and meta-analyses specifically addressing ASD remain scarce [28-30]. This study
contributes to the growing body of evidence and underscores the need for further rigorous research.
This study presents several limitations. First, the heterogeneity of the included studies - particularly
regarding intervention types, dosing regimens, and outcome measures - complicates direct comparisons and
meta-analysis. The impossibility of carrying out a meta-analysis is due to the lack of essential statistical
data in the primary studies, such as means, standard deviations, and interquartile ranges. Second, the small
sample sizes and substantial missing data further limit the reliability of the findings. Third, variation in
cannabinoid formulations across studies makes it difficult to assess their true efficacy and safety.
Additionally, methodological biases, particularly in patient selection and randomization, may have
influenced results. Finally, the limited number of high-quality RCTs on this topic restricts the strength of
the conclusions drawn.
Future research should focus on standardized methodologies, larger and more diverse patient populations,
and long-term safety evaluations. Further studies should also explore optimal dosing regimens and the
biological mechanisms underlying cannabinoids' effects in ASD.
Conclusions
This systematic review assessed the potential impact of cannabinoids on ASD symptoms and adverse effects.
While preliminary evidence suggests potential benefits, particularly for anxiety, sleep, and behavior, the
findings remain inconclusive due to study heterogeneity and methodological limitations. More rigorous,
well-designed RCTs are necessary to confirm these results and establish clear treatment guidelines for
cannabinoid use in ASD.
Additional Information
Author Contributions
All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the
work.
Concept and design: Lidia Cheidde, Danilo A. Pereira, Laura Cheidde, Mateus Daniel R. Megiolaro, Ana
Elisa F. Camargo, Victor G. Soares, Elizabet Taylor P. Weba, Anderson M. Pereira da Silva, Matheus Augusto
N. Fernandes, Rafael Triaca, Paula Maria P. Mimura, Pedro Paulo Ladeira Júnior, Dillan C. Amaral
Acquisition, analysis, or interpretation of data: Lidia Cheidde, Laura Cheidde, Mateus Daniel R.
Megiolaro, Ana Elisa F. Camargo, Victor G. Soares, Elizabet Taylor P. Weba, Anderson M. Pereira da Silva,
Matheus Augusto N. Fernandes, Rafael Triaca, Pedro Paulo Ladeira Júnior, Dillan C. Amaral
Drafting of the manuscript: Lidia Cheidde, Danilo A. Pereira, Laura Cheidde, Mateus Daniel R. Megiolaro,
Ana Elisa F. Camargo, Victor G. Soares, Elizabet Taylor P. Weba, Anderson M. Pereira da Silva, Matheus
2025 Pereira et al. Cureus 17(3): e80725. DOI 10.7759/cureus.80725 10 of 12

Augusto N. Fernandes, Rafael Triaca, Pedro Paulo Ladeira Júnior, Dillan C. Amaral
Critical review of the manuscript for important intellectual content: Lidia Cheidde, Danilo A. Pereira,
Laura Cheidde, Mateus Daniel R. Megiolaro, Ana Elisa F. Camargo, Victor G. Soares, Elizabet Taylor P. Weba,
Anderson M. Pereira da Silva, Matheus Augusto N. Fernandes, Rafael Triaca, Paula Maria P. Mimura, Pedro
Paulo Ladeira Júnior, Dillan C. Amaral
Supervision: Danilo A. Pereira, Paula Maria P. Mimura
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.
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