Supporting Cognitive Flexibility in Autism: Mechanistic Insights into Cannabinoid–Terpene Interactions

Autism spectrum conditions have been associated with alterations in synaptic transmission, critical period remodeling, and excitatory–inhibitory balance across distributed neural circuits. Converging evidence from genetic, electrophysiological, and animal model studies suggests that dysregulated activity-dependent synaptic plasticity—particularly altered long-term potentiation or long-term depression within hippocampal-cortical, cortico-striatal, and cerebellar networks—may contribute to reduced cognitive flexibility, repetitive behaviors, and difficulties in social and communicative adaptation. In this framework, core behavioral features of autism may reflect circuit-level persistence of previously-formed neural representations and altered updating of new information, rather than global neural dysfunction.Here we propose that modulating activity-dependent plasticity and excitatory–inhibitory dynamics may represent a plausible strategy for supporting cognitive flexibility in autism. Cannabinoids and terpenes derived from Cannabis sativa interact with multiple neural signaling systems—including CB1 receptors, GPR55, TRP channels, voltage-gated ion channels, serotonergic pathways, and endocannabinoid metabolism—that are known to influence synaptic transmission and plasticity. By engaging these convergent mechanisms, interactions among multiple botanical compounds may influence circuit-level excitability and synaptic plasticity processes implicated in autism.Within this framework, we consider a set of phytocompounds—comprising a dozen cannabinoids and terpenes—with documented interactions across neural signaling pathways that regulate synaptic plasticity and excitability. Together, this perspective provides a mechanistic rationale for how multi-compound cannabinoid–terpene interactions may influence neural circuit dynamics underlying cognitive flexibility in autism.