Where was this research published?

Published in Neurochemical research on August 27, 2026.

CBD THC Mental Health Addiction Epilepsy Neuroprotection Endocannabinoid

Could CBD offer a safer path for psychosis treatment?

Q: What did this Review find?

The review concludes that *CBD* has **limited abuse potential** compared with *THC*, which is identified as the main driver of cannabis dependence.

Q: What topics does this cannabis study cover?

This study covers research on: CBD, THC, Mental Health, Addiction, Epilepsy, Neuroprotection, Endocannabinoid.

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

Neurochemical research • August 27, 2026 • Review • Highly Relevant

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AI Summary

This review compares CBD with THC to explain why they have different effects and addiction risks. The abstract states that THC is the main driver of cannabis dependence, while CBD has limited abuse potential and is being investigated for conditions including cannabis use disorder, treatment-resistant epilepsy, and psychosis. Unlike THC, which activates CB1 and CB2 receptors, CBD can reduce or alter signaling at these receptors and also interacts with other targets involved in pain, inflammation, seizures, and neuroprotection.

The authors propose that CBD’s effects on cannabinoid and serotonin-related systems may help explain its potential in schizophrenia and stimulant-induced psychosis. In particular, its influence on 5-HT1A/2A receptors provides a mechanistic rationale for further study. However, this is a mechanistic review: the abstract does not report clinical trial results or quantitative evidence showing that CBD treats psychosis. For cannabis users, the key practical distinction is that CBD and THC are not pharmacologically interchangeable, and products containing THC may carry greater dependence-related risks.

💡 Key Findings

The review concludes that CBD has limited abuse potential compared with THC, which is identified as the main driver of cannabis dependence.

Good

65%

CBD differs from THC at cannabinoid receptors: it can act as a negative allosteric modulator of CB1 and an antagonist of THC’s effects, rather than simply activating these receptors.

Good

70%

The review identifies interactions with 5-HT1A/2A serotonin receptors and other nervous-system targets as a mechanistic rationale for exploring CBD in psychosis, including schizophrenia and stimulant-induced psychotic states.

Moderate

55%

The abstract reports no quantitative clinical outcomes or confirmed treatment effectiveness for psychosis, so CBD should be viewed as an investigational option rather than an established treatment.

High

90%

📄 Original 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.

Paper Type

📚 Review

Publication

Journal: Neurochemical research
Published: August 27, 2026
PMID: 42658346
DOI: 10.1007/s11064-026-04860-1

Authors (9)

Kazutoshi Yonemura Laboratory of Drug Addiction and Experimental Therapeutics, Department of Pharmacy, School of Pharmacy, Hyogo Medical University, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 650-8530, Japan.
Nobue Kitanaka Laboratory of Drug Addiction and Experimental Therapeutics, Department of Pharmacy, School of Pharmacy, Hyogo Medical University, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 650-8530, Japan.
Kazuo Tomita Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8544, Japan.
F Scott Hall Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, 43614, USA.
Moe Matsuo Laboratory of Drug Addiction and Experimental Therapeutics, Department of Pharmacy, School of Pharmacy, Hyogo Medical University, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo, 650-8530, Japan.
+4 more authors

MeSH Keywords

Humans Cannabidiol Animals Synaptic Transmission Receptor, Serotonin, 5-HT1A Endocannabinoids Receptor, Serotonin, 5-HT2A Psychotic Disorders Serotonin