📚 Background: ASD Neurobiology

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by:

• Deficits in social communication

• Restricted, repetitive patterns of behavior, interests, or activities

• Often accompanied by sensory sensitivities, anxiety, intellectual disability, or ADHD

Core Neurobiological Features:

• Glutamatergic dysfunction: Imbalance between excitatory (glutamate) and inhibitory (GABA) transmission

• Impaired synaptic plasticity

• Abnormalities in NMDA receptor functioning

• Default Mode Network (DMN) disruption

• Altered levels of BDNF, GABA, and mTOR signaling

These findings suggest a potential role for glutamatergic modulators like ketamine in addressing core and associated symptoms of ASD.

💊 Rationale for Ketamine Use in ASD

Ketamine is a noncompetitive NMDA receptor antagonist that:

• Enhances AMPA receptor throughput

• Boosts BDNF and mTOR activity, aiding neuroplasticity

• Modulates glutamate-GABA balance

• Can improve functional connectivity, especially in prefrontal cortex

These actions theoretically target some of the core neurodevelopmental disruptions observed in ASD.

🔬 Current Research and Clinical Findings

1. Animal Studies

• Rodent models of autism (e.g., valproate-induced, FMR1 knockout) have shown:

  • Improved social interaction

  • Normalization of hyperexcitability

  • Restoration of synaptic density and mTOR signaling

• Sub-anesthetic doses of ketamine reversed social deficits in multiple preclinical studies

2. Human Studies

➡️ Findings are preliminary but suggest short-term social engagement and emotional responsiveness improvements.

🔄 Ketamine Use in ASD: Possible Targets

⚠️ Cautions & Limitations

• Lack of large RCTs: Most studies are small, open-label, or animal-based.

• Transient effects: Benefits often last hours to days; maintenance protocols unstudied.

• Dissociation and overstimulation: Risk of sensory overload in ASD population.

• Ethical concerns: Especially in non-verbal or low-functioning individuals—informed consent and assent are critical.

🏥 Special Use Case: Ketamine for Catatonia in ASD

• ASD with catatonia is increasingly recognized, especially in adolescents.

• IV ketamine (0.3–0.5 mg/kg) has shown rapid resolution of mutism, stupor, posturing in multiple case reports.

• Often used when benzodiazepines fail or as a bridge to ECT.

🔮 Future Directions

• Ketamine analogs (e.g., arketamine, rapastinel) with fewer dissociative effects

• Intranasal/sublingual models for home-based administration

• Combining ketamine with behavioral therapies to enhance learning/social imprinting during windows of neuroplasticity

• Biomarker-based stratification: Using EEG/fNIRS to identify ASD subgroups that might benefit

🧾 Conclusion

While ketamine is not currently a standard treatment for autism spectrum disorder, it represents an intriguing area of research. Its glutamatergic modulation and plasticity-enhancing effects align well with known neurobiological deficits in ASD, particularly in addressing social cognition and emotional regulation.

Use in ASD-associated catatonia is more established and should be considered in emergency and resistant cases. However, broader psychiatric use in autism must await larger, controlled trials and development of safer, autism-adapted delivery models.