The Potential of Cannabidiol for the Treatment of Psychosis: Endocannabinoid Regulation of Serotonergic Neurotransmission via Serotonin 5-HT1A/2A Receptors

AI Summary

CBD is a non-competitive negative allosteric modulator of CB1 and antagonist of Δ9-THC, explaining low abuse liability and differing pharmacology.
CBD engages multiple CNS targets, including GPR55, TRPV1 and ENT1, mediating anticonvulsant, anti-inflammatory, analgesic and neuroprotective effects.
CBD modulates endocannabinoid regulation of serotonergic signalling via 5-HT1A and 5-HT2A receptors, supporting its potential in treating psychosis.

TL;DR (AI Generated)

Cannabis, widely used for both medical and non-medical purposes, primarily contains Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Δ9-THC is the main driver of cannabis abuse and of psychological and physical dependence, whereas CBD has limited abuse potential and is even being investigated as a treatment for cannabis use disorder and other conditions.

While Δ9-THC activates these receptors as an agonist, triggering Gi-coupled signaling cascades such as MAPK pathways and suppressing presynaptic monoamine release, CBD functions as a non-competitive negative allosteric CB1 modulator and non-competitive antagonist of Δ9-THC.

These diverse molecular actions are thought to underlie CBD's broad therapeutic potential across seizures and other CNS disorders, providing a mechanistic rationale for exploring CBD as a treatment option for psychosis in schizophrenia and stimulant-induced psychotic states.

Basic summary

Neurochem Res. 2026 Aug 27;51(5):251. doi: 10.1007/s11064-026-04860-1.

ABSTRACT

Cannabis, widely used for both medical and non-medical purposes, primarily contains Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD). Δ⁹-THC is the main driver of cannabis abuse and of psychological and physical dependence, whereas CBD has limited abuse potential and is even being investigated as a treatment for cannabis use disorder and other conditions. This review aims to clarify how the molecular and receptor-level mechanisms of CBD, compared with Δ⁹-THC, shape its distinct therapeutic profile and low liability for addiction, thereby informing the safer clinical application of CBD-containing interventions to schizophrenia. CBD exerts sedative and therapeutic effects, including in treatment-resistant epilepsy, and acts in part via CB1 and CB2 receptors that also mediate Δ⁹-THC actions. While Δ⁹-THC activates these receptors as an agonist, triggering Gi-coupled signaling cascades such as MAPK pathways and suppressing presynaptic monoamine release, CBD functions as a non-competitive negative allosteric CB1 modulator and non-competitive antagonist of Δ⁹-THC. These distinct intracellular signaling mechanisms are considered to underlie the markedly different pharmacological profiles and abuse liabilities of Δ⁹-THC and CBD. CBD also engages multiple CNS targets beyond CB1 and CB2, including GPR55, TRPV1 and ENT1, which are implicated in anticonvulsant, anti-inflammatory, analgesic and neuroprotective actions. Although GPR55 pharmacology remains controversial and Δ⁹-THC shows inconsistent activity at this receptor, converging evidence indicates that CBD can antagonize CB1/CB2 and modulate atypical cannabinoid-sensitive proteins. Excessive activation of certain serotonin receptors, including 5-HT_1A/2A, are thought to underlie some symptoms of psychosis. These diverse molecular actions are thought to underlie CBD’s broad therapeutic potential across seizures and other CNS disorders, providing a mechanistic rationale for exploring CBD as a treatment option for psychosis in schizophrenia and stimulant-induced psychotic states.

PMID:42658346 | DOI:10.1007/s11064-026-04860-1

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