Category Archives: Autism

Integrated network pharmacology and lipidomics provide insights into potential mechanisms underlying the effects of cannabidiol in a rat model of autism

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Cannabidiol (CBD) is being studied for its potential effects on biological pathways involved in autism, including inflammation, oxidative stress and lipid metabolism.

In this animal study, researchers combined network pharmacology with lipidomic analysis to investigate how CBD affected a rat model of autism. The results identified changes in multiple molecular targets and lipid pathways that may help explain CBD’s biological effects.

The findings provide new mechanistic clues about how CBD may influence processes associated with autism and support further investigation into its therapeutic potential.

“Background: Cannabidiol (CBD) has shown potential benefits in managing symptoms associated with autism spectrum disorder (ASD), although its underlying mechanisms of action remain unclear. This study investigated whether CBD improves ASD-like behavior in association with changes in lipid metabolic disturbances and apoptosis-related signaling in a prenatal valproic acid (VPA) rat model.

Methods: Male offspring from VPA-exposed rats received CBD (10 mg/kg, intraperitoneal, twice daily) for 7 days starting on postnatal day 21. Behavioral testing evaluated hyperactivity, social interaction, and repetitive behaviors. Hippocampal lipid profiles were quantified by UPLC-MS/MS. Candidate mechanisms were examined through a joint pathway analysis integrating lipidomics with curated target information, followed by targeted gene/protein validation (qPCR, Western blotting) and molecular docking.

Results: CBD treatment improved VPA-induced hyperactivity and repetitive behaviors and social interaction deficits. Lipidomics demonstrated remodeling of hippocampal lipid abnormalities after CBD treatment, with changes across major classes, including phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins. Joint pathway analysis pinpointed potential targets-LDHA, LDHB, PKM, PTGS2, and EPHX2-linked to energy-related pathways (pyruvate metabolism, glycolysis/gluconeogenesis, propanoate metabolism) and arachidonic acid metabolism. CBD also modulated apoptosis-related protein dysregulation, with potential involvement of Akt-related signaling. Docking results suggested possible binding between CBD and the selected targets.

Conclusion: These results suggest that CBD improves ASD-like behaviors alongside hippocampal lipid metabolism remodeling and modulation of apoptosis-related signaling in VPA-exposed rats, providing preliminary insights into potential mechanisms underlying the effects of CBD in ASD models.”

https://pubmed.ncbi.nlm.nih.gov/42632396

“CBD improved ASD-like behaviors in VPA-induced rats.”

https://www.sciencedirect.com/science/article/abs/pii/S0165178126004658?via%3Dihub

Δ9-Tetrahydrocannabinol Modulates Hippocampal Neurogenesis in Female Wistar Rats: Interaction with Estradiol

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THC may influence the female brain through both neurogenic and anti-inflammatory mechanisms. In ovariectomized female rats, Δ9-THC significantly increased hippocampal cell proliferation, showed evidence of enhanced neurogenesis, and reduced the inflammatory markers COX-2 and TNF-α. The effects also interacted with estradiol, highlighting the importance of hormonal status in determining THC’s actions in the brain.

“The endocannabinoid system (ECS) plays a key role in regulating neurogenesis and inflammatory processes in the brain.

The increasing prevalence of Cannabis use among women highlights the importance of understanding sex-specific effects of cannabinoids, particularly in the context of hormonal interactions.

This study aimed to investigate the effects of delta-9-tetrahydrocannabinol (THC) and estradiol benzoate (EB) on adult hippocampal neurogenesis (AHN) and inflammation in ovariectomized female Wistar rats.

Sixteen rats were allocated to four experimental groups receiving THC, EB, both treatments, and vehicle. Immunohistochemical analyses were conducted to evaluate markers of proliferation (Ki-67), neurogenesis (doublecortin and PSA-NCAM), cannabinoid receptor expression (CB1), and inflammation (COX-2 and TNF-α) in the hippocampal formation.

The administration of THC significantly increased Ki-67 immunoreactivity, suggesting enhanced cell proliferation. A trend toward increased doublecortin expression was observed, particularly in EB-treated animals. THC also modulated CB1 receptor expression, with significant increases in the dentate gyrus and hilus following combined THC and EB treatment. Furthermore, THC reduced inflammatory markers, with region-dependent decreases in COX-2 and TNF-α expression.

These findings indicate that THC influences markers associated with hippocampal cell proliferation, neurogenesis, cannabinoid signaling and inflammation in female rats, and that some of these effects depend on estradiol status.

The interaction between cannabinoids and gonadal hormones may represent an important mechanism underlying sex-specific neurobiological responses and suggests potential targets for therapeutic intervention in neuropsychiatric disorders.”

https://pubmed.ncbi.nlm.nih.gov/42570151

https://link.springer.com/article/10.1007/s11064-026-04857-w


NTI164, a novel medicinal cannabis extract, improves core symptoms of autism spectrum disorder: Results from a double-blind, randomised, controlled trial (The Harmony study)

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Current medications for autism spectrum disorder generally target associated symptoms rather than the core features of ASD. In this randomized, double-blind, placebo-controlled Phase II/III trial, the full-spectrum medicinal cannabis extract NTI164 significantly improved overall clinical severity, adaptive functioning, social responsiveness, mood, anxiety, and family quality of life in children and adolescents with moderate-to-severe ASD, while demonstrating an excellent safety profile.

“Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder, characterised by difficulties with communication, social interaction, repetitive behaviours, restricted interests, and varying levels of intellectual disability. Aetiology remains unclear for many patients and the underlying physiology is complex. Approved pharmacological treatments of ASD target irritability, temper tantrums, and agitation, with no therapies targeting core ASD symptoms.

This double-blind, randomised, placebo-controlled Phase II/III clinical trial investigated the efficacy and safety of NTI164, a novel full-spectrum medicinal cannabis product with <0.3% tetrahydrocannabinol (THC), in paediatric patients with Level II/III ASD.

Participants were recruited from a tertiary paediatric neurology clinic and randomised to receive NTI164 up to 20 mg/kg/day or placebo for an 8-week double-blind phase; participants receiving placebo were able to receive NTI164 in an 8-week open label phase following the double-blind phase. Safety assessments, clinician-, and caregiver-rated tools measuring symptoms were utilised at baseline and Week 8. Analysis of Covariance (ANCOVA) was used for statistical analyses.

NTI164 demonstrated an excellent safety profile, and statistically significant and meaningful improvements compared to placebo in overall clinical severity, adaptive functioning, social responsiveness, and affective symptoms. Caregivers also reported improved family experiences and quality of life with NTI164. Participants who transitioned from placebo to NTI164 open label reported similar improvements as those reported during the double-blind phase.

NTI164 significantly improved core and associated symptoms of ASD compared to placebo.

Consistent benefits reported by both clinicians and caregivers in both open label and double-blind contexts supports further clinical development of NTI164 in ASD.”

https://pubmed.ncbi.nlm.nih.gov/42561512

“The multi-domain improvements observed with NTI164 treatment compared to placebo reported in this study support utility as a broader therapeutic intervention which can address ASD symptoms.

This randomised, double-blind, placebo-controlled clinical trial in children and adolescents with moderate-severe ASD showed NTI164 meaningfully improves global impression of clinical severity, adaptive functioning, aspects of social responsiveness, mood, anxiety, and family experiences, with an excellent safety profile.”

https://www.neurotherapeuticsjournal.org/article/S1878-7479(26)00203-5/fulltext


UK Medical Cannabis Registry: A Clinical Outcomes Analysis for Autism Spectrum Disorder

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“Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with distressed behaviors and psychological challenges. This study aims to evaluate the change in health-related quality of life (HRQoL), anxiety, and sleep quality in autistic individuals prescribed cannabis-based medicinal products (CBMPs).

Method: This observational case series analyzed data from the UK Medical Cannabis Registry on autistic adults treated with CBMPs. Demographic and clinical data were collected at baseline, with patient-reported outcome measures assessed up to 18 months. Primary outcomes included changes in anxiety (GAD-7), sleep quality (SQS), and HRQoL (EQ-5D-5L). Secondary outcomes included the incidence of adverse events. Statistical significance was indicated by p < 0.050.

Results: One-hundred and thirty individuals met the inclusion criteria. GAD-7 (p < 0.001) and SQS (p < 0.001) scores improved from baseline to 18 months. EQ-5D-5L index values showed improvement from baseline (0.43 ± 0.30) to 18 months (0.51 ± 0.32, p < 0.001), and PGIC scores increased from 1 month (5.43 ± 1.49) to 18 months (5.65 ± 1.32, p = 0.013). Twenty-five participants (19.23%) reported a total of 232 (178.46%) adverse events, with most being mild (n = 88; 67.69%) or moderate (n = 99; 76.15%).

Conclusion: Treatment with CBMPs was associated with improvements in HRQoL, anxiety, and sleep outcomes in autistic patients over an 18-month period. Given the absence of a control group, these findings represent associations rather than proven treatment effects. Further high-quality randomized controlled trials are needed to confirm the long-term efficacy and safety of CBMPs in ASD.”

https://pubmed.ncbi.nlm.nih.gov/42387975

“The endocannabinoid system (ECS) is a widespread neuromodulatory network that has been linked to the pathophysiology of ASD and is viewed as a potential target for drug development.”

“This observational study suggests that CBMP initiation in autistic adults is associated with improvements in HRQoL, anxiety, and sleep quality over 18 months. There was a favorable safety profile, with 80.77% of patients not reporting any adverse events.”

https://onlinelibrary.wiley.com/doi/10.1002/npr2.70146

Efficacy and Safety of Cannabinoid-Based Products in Children and Adolescents with Autism Spectrum Disorder, Fragile X Syndrome and Rett Syndrome: A Systematic Review

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“Introduction: Neurodevelopmental disorders (NDDs), including Autism Spectrum Disorder (ASD), Fragile X syndrome (FXS), and Rett Syndrome (RTT), share impairments in cognitive and behavioral functioning and may involve an altered excitatory/inhibitory balance modulated by the endocannabinoid system. This systematic review evaluated the safety and efficacy of cannabinoid-based products (CBPs) in these pediatric NDDs.

Methods: We conducted a systematic review according to Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) 2020, including randomized and nonrandomized studies of patients under 18 years treated with cannabidiol (CBD), cannabidivarin (CBDV), tetrahydrocannabinol (THC), or their combinations. Outcomes were adverse events (AEs) and treatment discontinuation, seizure reduction, and behavioral and cognitive changes. Study quality and certainty of evidence were assessed using design-specific risk-of-bias tools and the GRADE approach.

Results: Seventeen studies (two randomized controlled trials, observational studies, and case series) met the inclusion criteria. Across diagnoses, CBPs were generally associated with mild-to-moderate AEs and low discontinuation rates. Descriptive pooled proportions suggested behavioral improvements in ASD and FXS and seizure reduction in RTT, with exploratory analyses indicating differential effects of CBD versus CBD + THC on behavioral and cognitive outcomes in ASD.

Conclusion: CBPs may offer potential benefits for selected behavioral symptoms and comorbid epilepsy in pediatric NDDs, but current evidence is insufficient to support routine clinical use. High-quality randomized controlled trials with standardized outcome measures and long-term follow-up are needed to clarify efficacy, safety, and syndrome-specific effects.”

https://pubmed.ncbi.nlm.nih.gov/42339654

https://journals.sagepub.com/doi/10.1177/10445463261462382

Long-term follow-up of children with autism spectrum disorder and severe treatment-resistant behavioral symptoms treated with purified cannabidiol

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“Background: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition often associated with severe behavioral disturbances and limited pharmacological treatment options. Cannabidiol (CBD) has emerged as a potential therapeutic option; however, evidence on its long-term effectiveness and safety in children with ASD is scarce.

Objective: To evaluate the long-term effectiveness and safety of purified CBD as addon therapy in children with severe ASD and treatment-resistant behavioral symptoms.

Material and methods: We conducted a prospective observational before-and-after study in children and adolescents (3-18 years) with ASD severity levels 2 or 3 and intellectual disability treated with add-on CBD. The primary outcome was change in caregiver-identified symptoms, while secondary outcomes included standardized behavioral scales (Repetitive Behavior Scale-Revised [RBS-R], Vineland Adaptive Behavior Scales-II maladaptive behavior domain, Aberrant Behavior Checklist [ABC], Pediatric Sleep Clinical Global Impressions-Severity, Autism Family Experience Questionnaire, and Parental Stress Scale). Safety and tolerability were assessed through caregiver-reported adverse events.

Results: Twenty children were enrolled, of whom 13 completed the long-term follow-up (mean 27.6 ± 1.3 months). Of the caregiver-identified symptoms, improvements observed during the initial short-term study were maintained or further improved during follow-up. Standardized scales showed modest but sustained improvements, particularly in irritability, social withdrawal, and hyperactivity. Mild, transient adverse events, mainly irritability or decreased appetite, did not recur during long-term followup, and concomitant medications were reduced in 40% of patients.

Conclusion: Long-term treatment with purified CBD in children with severe ASD was well tolerated and associated with sustained improvement in caregiver-reported outcomes and standardized scales.”

https://pubmed.ncbi.nlm.nih.gov/42248366

“Cannabidiol (CBD), a non-psychoactive cannabinoid, has gained increasing interest as a potential therapeutic option for both core symptoms of ASD and associated comorbidities, based on its anxiolytic, anti-inflammatory, and neuromodulatory properties, together with a generally favorable safety profile.”

“In this long-term follow-up of children with severe ASD treated with purified CBD, no significant differences were observed between the three-month and the 26-month evaluations, suggesting that the initial improvements were maintained over time. Among patients who completed the extended follow-up, purified CBD was well tolerated and associated with sustained improvement in several symptoms, particularly those identified by families as most disruptive in daily life.”

https://www.sciencedirect.com/science/article/abs/pii/S0091305726000754?via%3Dihub

CBD-Rich Cannabis Therapy in Children with Autism Spectrum Disorder May Improve Symptoms of Hyperactivity and Attention Deficit: An Open-Label Study

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“Introduction: Medical cannabis has gained growing attention as a potential treatment for children with Autism Spectrum Disorder (ASD), particularly in cases where conventional pharmacological approaches have proven ineffective. Emerging evidence suggests that cannabinoid-based therapies may alleviate Attention Deficit Hyperactivity Disorder (ADHD) related symptoms in children with ASD. The objective of this study is to evaluate changes in ADHD symptoms over six months of treatment with a CBD-rich cannabis oil, using the Conners’ Teacher Rating Scale as the assessment tool.

Methods: This was a prospective, single-arm, open-label study conducted at a single center. A total of 109 children and young adults diagnosed with ASD and ADHD symptoms were recruited between November 2019 and April 2021. Of these, 53 participants were assessed by their schoolteachers using the Conners’ Teacher Rating Scale (CTRS) questionnaire, both before and after a three- to sixmonth treatment period with a CBD-rich, cannabis oil-based product. Blood samples were collected before and after treatment to measure cannabinoid levels, including CBD, 6-OH-CBD, 7-COOHCBD, and 7-OH-CBD.

Results: Significant improvements were observed in the following categories: anxious-shyness, perfectionism, ADHD index, emotional lability, and hyperactivity-impulsivity (p < 0.001). Additional trends toward improvement were identified in oppositional behavior (p = 0.009), cognitive inattention (p = 0.009), hyperactivity (p = 0.006), the Conners’ Global Index (p = 0.007), and DSM-IV inattention scores (p = 0.003). No significant correlations were found between cannabinoid dosage or blood levels and changes in CTRS scores, except for emotional lability, where higher CBD concentrations were predictive of greater symptom improvement.

Discussion: This is the first prospective study to evaluate the effects of CBD-rich cannabis on ADHD symptoms in children with ASD using standardized teacher-based Assessments (CTRS). The findings indicate improvements in core behavioral domains. While previous studies have focused primarily on parent-reported outcomes or small-scale trials, our results support emerging evidence on the role of cannabinoids in modulating attention and emotional regulation. The main limitations of the study were its open-label design.

Conclusion: CBD-rich cannabis oil may reduce ADHD symptoms in children with ASD. These findings support the need for future clinical trials to validate efficacy and determine optimal dosing.”

https://pubmed.ncbi.nlm.nih.gov/41503912

https://www.eurekaselect.com/article/152283

Cannflavin B ameliorates behavioural and neuronal systems alterations in adolescent rats exposed to prenatal valproic acid

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“Currently, no pharmacological treatments ameliorate the core and comorbid symptoms of autism spectrum disorders, but solely target comorbid symptoms such as irritability, anxiety, and epilepsy.

There has been growing interest in using whole cannabis or cannabidiol as potential therapeutics in autism. However, there are concerns surrounding the use of whole cannabis in children, and reports examining the therapeutic efficacy of cannabidiol are inconsistent.

In this study, the potential therapeutic efficacy of cannflavin B, a non-psychoactive component of the Cannabis sativa plant, was evaluated. Using prenatal valproic acid (VPA) exposure in rats, a model widely used to study aspects of autism, sex differences in adolescent behaviour, neuronal oscillatory changes, and microglial activity in response to cannflavin B administration (0.2 mg/kg, i.p.) were assessed.

Cannflavin B was well tolerated and ameliorated most of the observed VPA-induced changes.

Cannflavin B had anxiolytic-like properties in female VPA rats, and normalized sociality in VPA animals of both sexes.

Within the prefrontal cortex, cingulate cortex, and hippocampus, most of the VPA-induced regional responses in neuronal oscillatory spectral power, coherence, and theta-gamma cross-frequency synchrony were ameliorated by cannflavin B. Cannflavin B also attenuated the sex- and brain region-specific VPA-induced elevations in the microglial marker Iba1. In vitro, cannflavin B normalized VPA-induced elevations in cortical and hippocampal neuronal activity and promoted more organized cortical firing.

These findings demonstrate cannflavin B ameliorates behavioural and neuronal systems function alterations induced by prenatal VPA in rats, and highlights the importance of researching alternative cannabis compounds in autism and other disorders.”

https://pubmed.ncbi.nlm.nih.gov/41496357

“Like THC and CBD, cannflavins are most likely highly lipophilic based on their prenylated structure, indicating that they should be able to readily cross the blood brain barrier.”

“In conclusion, this was the first study to examine the in vivo effects of cannflavin B in a model widely used to study aspects of autism. It was demonstrated that cannflavin B administration, a non-psychoactive component of the Cannabis sativa plant, could normalize many of the sex-dependent and independent alterations in behaviour and neuronal activity, as well as microglial marker levels, in adolescent rats following prenatal exposure to VPA. Cannflavin B, at the dose used, appeared to be well tolerated with no adverse effects observed.”

https://www.sciencedirect.com/science/article/pii/S0753332225011436?via%3Dihub


A Balanced Cannabinoids Mixture Protects Neural Stem/progenitor Cells from CoCl2 Induced Injury by Regulating Autophagy and Inflammation: An in Vitro Study

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“Although tetrahydrocannabinol (THC) and cannabidiol (CBD) have been individually studied for their neuroprotective roles, few studies have addressed the effects of their balanced 1:1 formulation Satinex (STX) under pathologic conditions like hypoxia. Moreover, the effect of STX on embryonic neural stem/progenitor cells (ENS/PCs) derived from the rat embryonic brain, which are highly vulnerable during early development, remains unexplored.

Considering the pivotal role of hypoxia in numerous neuropathological situations, this study examined the impact of STX on rat ENS/PCs exposed to chemically induced hypoxia.

ENS/PCs were isolated from rat embryos and subjected to hypoxia using 100 µM cobalt (II) chloride hexahydrate (CoCl₂0.6 H₂O) for 48 h. Cytotoxic activity of STX andCoCl2was assessed using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2 H-tetrazolium (MTT) assay, while stem cell identity was confirmed via flow cytometry (Nestin, SOX2). STX (0.1 and 0.5 µM) was applied under both normoxic and hypoxic conditions. Expression levels of hypoxia-inducible factor 1-alpha (Hif1α) mRNA, autophagy markers (Beclin-1, microtubule-associated protein 1 light chain 3-II [LC3-II]), and pro-inflammatory proteins nuclear factor kappa B [NF-κB], Toll-like receptor 2 [TLR2], Toll-like receptor 4 [TLR4]) were assessed using reverse transcription polymerase chain reaction (RT-PCR) and western blot techniques following STX treatment.

Based on flow cytometric assays, over 70% of cultivated cells were positive for Nestin and SOX2. Hypoxia significantly reduced cell viability and proliferation, accompanied by increased Hif1α mRNA expression. Treatment with STX (0.1 µM and 0.5 µM) significantly reversed these changes, restoring cell viability and proliferation while reducing Hif1α levels. Hypoxia also elevated autophagy markers (Beclin-1, LC3-II) and pro-inflammatory proteins (NF-κB, TLR2, TLR4), which STX suppressed in a dose-dependent manner.

This study provides novel evidence that STX mitigates hypoxia-induced neural damage by downregulating Hif1α and its downstream inflammatory and autophagic signaling pathways. The use of a clinically relevant cannabinoids mixture and a developmentally sensitive cell model underline the translational potential of balanced THC/CBD formulations in the treatment of hypoxia-related neurodegenerative and neurodevelopmental conditions.”

https://pubmed.ncbi.nlm.nih.gov/41240218

https://link.springer.com/article/10.1007/s12640-025-00770-2

Acute effects of cannabis on core and co-occurring features associated with autism spectrum disorder in adults

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“Pharmacological interventions that treat core and co-occurring features of autism spectrum disorder (ASD) are a persistent unmet need.

As such, use of cannabis to manage ASD features is common in the autistic community. Yet, few studies have examined the acute effects of cannabis on symptoms associated with ASD. Therefore, we measured changes in symptom ratings from before to after cannabis use in a sample of 111 self-identified autistic adults.

Anonymized archival data sourced from the Strainprint® app were analyzed. A subset of tracked information that reflected changes in core and co-occurring symptoms associated with ASD (i.e., Sensory Sensitivity, Repetitive Behaviors, Mental Control, and Negative Affect) were used to assess the impacts of cannabis on symptom severity.

Overall, symptom severity ratings were reduced by 73.09% from before to after cannabis use. More severe symptoms were associated with greater reductions in severity ratings after use.

Higher doses predicted greater reductions in severity of Repetitive Behaviors, Mental Control, and Negative Affect but dose of cannabis used to manage all symptoms remained static across time.

Results from this first empirical examination of the perceived acute effects of cannabis in autistic adults suggest that cannabis provides temporary relief from symptoms associated with ASD.”

https://pubmed.ncbi.nlm.nih.gov/41233406/

“The present study represents the first to demonstrate acute perceived beneficial effects of inhaled cannabis on core and co-occurring symptoms associated with ASD in a large adult sample.”

“These findings indicate that well-powered placebo-controlled trials are warranted to examine the acute effects of various cannabinoids and manipulations of the endocannabinoid system on ASD symptoms.”

“In sum, data from clinical trials of children and adolescents presents an evidence base that supports a continued focus on the impact of CBD on ASD features, while the present data from cannabis-using autistic adults indicates that a sole focus on CBD may not fully capture the potential impact of cannabinoids as a pharmacological intervention for adults with ASD. Thus, additional placebo-controlled clinical trials are needed where THC, CBD, and other non-intoxicating cannabinoids (e.g., cannabigerol), terpenes, and/or medications that modulate the functioning of the endocannabinoid system are administered to autistic adults to determine their relative effects on symptoms associated with ASD.”

https://www.nature.com/articles/s41598-025-23472-3