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Review
. 2025 Apr 21;7(1):21.
doi: 10.1186/s42238-025-00277-9.

Effect of cannabinoids on glutamate levels in the human brain: a systematic review and meta-analysis

Berzenn Urbi  1 , Vincent Sapaen  2 , Ian Hughes  2 , Maame Amma Owusu  2 , Arman Sabet  3   4 , Simon A Broadley  3   4
Affiliations
Review

Effect of cannabinoids on glutamate levels in the human brain: a systematic review and meta-analysis

Berzenn Urbi et al. J Cannabis Res. .

Abstract

Increased extracellular glutamate concentrations in the brain can cause neuronal injury. Cannabinoid use has been demonstrated to reduce extracellular glutamate levels in the brain in many animal models. However, there are no systematic reviews published evaluating the effect of cannabis on glutamate levels in the human brain. This review aimed to review studies that investigated the effect of cannabinoids on glutamate levels in the living human brain using neuroimaging methods and to provide evidence gathered from biomedical databases such as MEDLINE and EMBASE. Nine randomized controlled trials (RCTs) and ten observational studies met the eligibility criteria for this review. The articles included in the meta-analyses had a low risk of bias. Meta-analysis showed cannabis intake has no effects on the glutamate levels in human brain. However, there is limited evidence indicating that oral cannabidiol and cannabidivarin increased the glutamate/glutamine ratio in the basal ganglia while intravenous and vaped tetrahydrocannabinol increased glutamate in the basal ganglia. There is also some evidence showing oral cannabidiol increased glutamate in the hippocampus. Most of the observational studies in this review demonstrated a reduction in glutamate in the brain of chronic cannabis users. However, these findings are not definitive and will require further confirmations. This review suggests that acute cannabis administration may increase glutamate in the basal ganglia and hippocampus but not in other parts of the brain, while chronic cannabis use lead to a decrease in glutamate levels in some parts of the brain. The quality of this evidence is limited therefore further studies are needed.

Keywords: Cannabis; Glutamate; Neurodegenerative disorder; Neuroimaging; Psychosis.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The search process and criteria for excluding articles according to the PRISMA flow diagram
Fig. 2
Fig. 2
Overall risk of bias using Cochrane’s risk of bias (ROB) for randomized studies
Fig. 3
Fig. 3
Meta- analysis of Glu (Basal Ganglia) n = 60; p = 0.954
Fig. 4
Fig. 4
Meta- analysis of Glu (Cortex) n = 92; p = 0.326
Fig. 5
Fig. 5
Meta- analysis of Glu (Hippocampus) n = 128; p = 0.232
Fig. 6
Fig. 6
Meta- analysis of Glu (Hippocampus, CBD treatment) n = 96; p = 0.102
Fig. 7
Fig. 7
Meta- analysis of Glx (Basal Ganglia) n = 110; p = 0.246
Fig. 8
Fig. 8
Meta- analysis of Glx (Cortex) n = 146; p = 0.900
Fig. 9
Fig. 9
Meta- analysis of Glx (PFC) n = 99; p = 0.614
Fig. 10
Fig. 10
Meta- analysis of Glx (Hippocampus) n = 128; p = 0.170
Fig. 11
Fig. 11
Meta- analysis of Glx/Cre (Basal Ganglia) n = 60; p = 0.726
Fig. 12
Fig. 12
Meta- analysis of Glu/Cre (Basal Ganglia) n = 80; p = 0.421
Fig. 13
Fig. 13
Meta-analysis of Glu/Cre (Cortex) n = 52; p = 0.804
See this image and copyright information in PMC

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