Does Prozac increase glutamate? (3+ clinical evidence)

In this article, we will discuss whether Prozac (fluoxetine) increases the glutamate release. Prozac is a popular SSRI (selective serotonin reuptake inhibitor) antidepressant used in the treatment of major depressive disorder (MDD), panic attacks, obsessive-compulsive disorder (OCD), and premenstrual dysphoric disorder (PMDD).

Does Prozac increase glutamate?

No, Prozac does not cause an increase in glutamate release, rather it decreases the glutamate release to induce the antidepressant effect in the patient. Prozac is known to increase the serotonin level and decrease the glutamate level and GABA.

What is the clinical evidence of Prozac’s effect on glutamate levels?

Glutamate is a free amino acid found in the brain. Glutamate transporters continuously remove glutamate from the brain’s extracellular fluid to prevent glutamate receptors from becoming overactivated. Moreover, glutamate in the blood is prevented from reaching the brain through the blood-brain barrier (1).

Clinical evidence suggests that Prozac has a broader binding profile, including 5HTRs and ion channels. The existence of several Prozac binding sites indicates that the drug may exert its antidepressant activity via different pathways.

One of the in vitro experimental data suggested that Prozac does not exert any effect on the EAAT3 (excitatory amino acid transporters) activity, but rather exerts its antidepressant effect by affecting GABAergic transmission nonspecifically. Eaat3, present in the plasma membrane of neurons and glial cells, helps in the extracellular uptake of glutamate and prevents glutamate-induced neuronal damage (2). However, modern research and experimental data suggest otherwise.

In chronic stress, the level of glutamate increases which ultimately leads to the atrophy of apical dendrites. Although the primary mechanism of action of Prozac is based on serotonergic system modulation, the final pathway appears to be the glutamatergic system (3). 

Prozac inhibits glutamatergic and gamma-aminobutyric acid (GABA)-ergic synaptic release by reducing the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex function.  On the flip side, it increases the extracellular serotonin level by the inhibition of SERT (serotonin transport) (3). 

In another in vivo analysis, the authors established that Prozac therapy lowered the total quantity of glutamate and GABA transporters at individual synapses in primary cortical neurons (4).

What is the role of Prozac in ‘excitotoxicity’?

Glutamate exerts excitatory effects on nerve cells and can drive cells to death, a process known as ‘excitotoxicity’. It can occur due to excessive glutamate exposure or overstimulation of its membrane receptors, which results in neuronal harm or death (5).

Prozac alters the expression of glutamatergic receptor subunits. It inhibits the NMDA (N-methyl-D-aspartate) receptors, a glutamate receptor and ion channel found in the neurons, and may provide neuroprotection by modulating glutamatergic involvement in excitotoxicity (6). 

Prozac has been reported to prevent excitotoxicity-induced oxidative stress and mitochondrial membrane potential impairment by preventing NO (nitric acid) and ROS (reactive oxygen species) production in mice (7).

Which medicines to avoid with Prozac?

Glutamate is essential for maintaining optimal energy levels, which are required for most CNC processes such as learning and memory, as well as neuroplasticity, which is required for adaptability to environmental changes (8). When it exceeds a certain concentration it can lead to toxicity and brain cell death.

Always take your medication of Prozac on time to avoid such circumstances. Also, avoid the use of monosodium glutamate (MSG, sodium salt of glutamic acid) under normal or stress conditions, especially if taking Prozac. 

Do not combine Prozac with certain medications including MAOI (monoamine oxidase inhibitor), certain antipsychotics, tricyclic antidepressants, and Vyvanse. It can result in a serious condition of serotonin syndrome. 


Call your doctor if you feel a sudden feeling of excitement, enthusiasm, restlessness or a state of euphoria. Bleeding gums, bruises and blood in cough are also reported serious side effects of the drug. Always consult your doctor before taking antidepressants and follow the dosage regimen strictly. 

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Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. Journal of neural transmission. 2014 Aug;121:799-817.


Park HJ, Baik HJ, Kim DY, Lee GY, Woo JH, Zuo Z, Chung RK. Doxepin and imipramine but not fluoxetine reduce the activity of the rat glutamate transporter EAAT3 expressed in Xenopus oocytes. BMC anesthesiology. 2015 Dec;15(1):1-7.


Lazarevic V, Mantas I, Flais I, Svenningsson P. Fluoxetine suppresses glutamate-and GABA-mediated neurotransmission by altering SNARE complex. International Journal of Molecular Sciences. 2019 Aug 30;20(17):4247.


Lazarevic V, Mantas I, Flais I, Svenningsson P. Fluoxetine suppresses glutamate-and GABA-mediated neurotransmission by altering SNARE complex. International Journal of Molecular Sciences. 2019 Aug 30;20(17):4247.


Mattson MP. Excitotoxicity. Neurodegeneration. 2017 Mar 29:37-45.


Beshara S, Beston BR, Pinto JG, Murphy KM. Effects of fluoxetine and visual experience on glutamatergic and GABAergic synaptic proteins in adult rat visual cortex. Eneuro. 2015 Nov 1;2(6).


Ludka FK, Dal-Cim T, Binder LB, Constantino LC, Massari C, Tasca CI. Atorvastatin and fluoxetine prevent oxidative stress and mitochondrial dysfunction evoked by glutamate toxicity in hippocampal slices. Molecular Neurobiology. 2017 Jul;54:3149-61.


Pal MM. Glutamate: The master neurotransmitter and its implications in chronic stress and mood disorders. Frontiers in human neuroscience. 2021 Oct 29;15:722323.

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