The Potential of Cannabidiol for the Treatment of Psychosis: Endocannabinoid Regulation of Serotonergic Neurotransmission via Serotonin 5-HT1A/2A Receptors.
Kazutoshi Yonemura, Nobue Kitanaka, Kazuo Tomita, F Scott Hall, Moe Matsuo, Kento Igarashi, Tomoaki Sato, George R. Uhl, Junichi Kitanaka
Neurochemical Research August 27, 2026 DOI: 10.1007/s11064-026-04860-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Cannabis CBD Serotonin |
| Keywords | Gpr55 Pharmacotherapy Schizophrenia Serotonin neurotransmission |
| Key findings | The authors argue that CBD's distinct receptor-level actions—non-competitive negative allosteric modulation of CB1, non-competitive antagonism of Δ9-THC, and engagement of GPR55, TRPV1, and ENT1—explain its broad therapeutic profile and low addiction liability compared with Δ9-THC. They propose this provides a mechanistic rationale for exploring CBD as a treatment for psychosis in schizophrenia and stimulant-induced psychotic states, while noting that GPR55 pharmacology remains controversial. |
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-HT1A/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.
Comparable studies
Other narrative reviews on CBD, most cited first.
Citations in the library
Cites 12
- Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis Proceedings of the National Academy of Sciences December 13, 2005
- Cannabinoids Elicit Antidepressant-Like Behavior and Activate Serotonergic Neurons through the Medial Prefrontal Cortex Journal of Neuroscience October 24, 2007
- 5-HT2A receptors: Pharmacology and functional selectivity. Pharmacological Reviews April 23, 2025
- Does cannabidiol reduce the adverse effects of cannabis in schizophrenia? A randomised, double-blind, cross-over trial. Neuropsychopharmacology November 2025
- Assessing Cannabis Use in People with Psychosis Cannabis and Cannabinoid Research February 1, 2024
and 7 more in the library