The Supplementation With The Amino Acid GABA Can Reduce SARS-CoV-2 Severity And Risk Of Mortality


A new study led by researchers from University of California, Los Angeles – USA and also involving scientists from Keck School of Medicine of the University of Southern California – USA involving murine models has found that supplementation with the inexpensive amino acid GABA (Gamma-aminobutyric acid) can reduce SARS-CoV-2 viral loads and also help reduce COVID-19 severity and also risk of mortality.

Gamma-aminobutyric acid) or GABA is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. 

The study findings were published in the peer reviewed journal: Frontiers In Immunology.

Our studies demonstrated that GABA administration initiated immediately, or two-day post-SARS-CoV-2 infection, reduced the lung coefficient index, lung viral load, pneumonitis, and death rate in SARS-CoV-2-infected K18-hACE2 mice. These results, along with our previous findings in the MHV-1 infected A/J mice, are the first reports of GABA administration modulating the outcome of viral infections.

The ability of GABA treatment to limit the disease severity following infection with two biologically distinct and lethal coronaviruses in different mouse strains suggests that GABA-R activation may be a generalizable therapeutic strategy to help reduce the severity of coronavirus infections, at least in mice.

Our observations are surprising in a number of ways. First, based on GABA’s anti-inflammatory actions in models of autoimmune disease, cancer, and parasitic infection, it was highly possible that early GABA treatment could have exacerbated the disease in SARS-CoV-2 infected mice by limiting or delaying the innate immune responses to the viral infection.

However, SARS-CoV-2-infected mice that received GABA treatment at the time of infection, or 2-days post-infection, fared much better than their untreated SARS-CoV-2-infected counterparts.

Second, GABA’s ability to modestly reduce viral load in the lungs was surprising. This indicates that GABA-R mediated changes in the intracellular ionic milieu modulate processes involved in SARS-Cov-2 entry, replication, and/or egress. We know from large-scale screens of drug libraries that GABA-R agonists do not interfere with SARS-CoV-2 binding to ACE2 or its internalization into cultured Vero E6 cells (69).

Notably, GABAA-Rs are expressed by lung bronchial and alveolar cells (32, 33, 70) and it is possible that GABAA-R activation led to changes in intracellular ion levels that made the environment less favorable for viral replication. While the activation of neuronal GABAA-Rs leads to Cl- influx and hyperpolarization, the activation of GABAA-Rs on other types of cells, such as alveolar ATII cells, causes Cl- efflux and depolarization (32, 33).

Many viruses, including some coronaviruses, can promote Ca2+ influx into their host cell to enhance their replication (71, 72). The activation of GABAA-Rs on infected cells could promote Cl- efflux which would oppose Ca2+ influx and reduce Ca2+ contents, limiting SARS-CoV-2 replication.

Indeed, calcium blockers have been shown to reduce SARS-CoV-2 replication in vitro, but whether they confer beneficial effects to COVID-19 patients has been controversial (73–75).

The activation of GABAA-Rs on alveolar and large airway epithelial cells may also have altered

1) the secretion of inflammatory signaling molecules from infected cells,

2) alveolar surfactant production/absorption, and/or

3) altered inflammatory responses and autophagy processes (17) in ways that limited virus infection and replication.

Third, while there has been some characterization of GABA’s effects on immune cell cytokine and chemokine secretion in models of autoimmune disease and cancer, little is known about GABA’s effects on anti-viral responses. We observed that GABA treatment shifted some cytokine and chemokine levels in directions that are expected to be beneficial if extended to COVID-19 treatment. Early GABA treatment elevated type 1 interferons in some mice. Since delayed or reduced type I interferon responses are a risk factor for developing severe COVID-19 (76), such tendencies could be beneficial.

GABA treatment significantly reduced circulating TNFα levels in infected mice, extending previous observations that GABA inhibits the NF-κB activation in mouse and human immune cells (7, 21). As a result, GABA treatment slightly decreased mean serum IL-6 from 10.7 to 6.3 pg/mL.

Since TNFα and IL-6 are important pro-inflammatory mediators, the decreased levels of circulating TNFα and IL-6 indicated that GABA treatment suppressed innate immune responses, which is likely to have contributed to its protective effects.

GABA-treated mice also had reduced levels of serum IP-10, a pro-inflammatory chemokine that attracts the migration of CXCR3+ macrophages/monocytes, T cells, and NK cells (77). Elevated levels of IP-10 are consistently detected in severely ill COVID-19 patients and may provide a predictive marker of patient outcome (78–81).

IP-10 production is induced by IFNγ, NF-κB activation and other stimulators in several types of cells (82). Consistent with the reduced IP-10 levels, we also found that the serum mean IFNγ level in the GABA-treated mice was about half that in the untreated SARS-CoV-2 infected mice (4.0 vs. 9.8 pg/mL).

These data suggest that early GABA treatment reduced IFNγ production and together with its inhibition of NF-κB activation, led to decreased IP-10 secretion. Given that IP-10 functions to recruit inflammatory cell infiltration into lesions and modulates cell survival, the lower levels of circulating IP-10 in GABA-treated mice are likely to have limited the migration of macrophages, monocytes, and NK cells into the pulmonary lesions and helped to protect the mice from death.

Similarly, we also observed that GABA treatment slightly reduced the levels of serum CCL2 which may have contributed to protecting mice from death since high levels of CCL2 are associated with high mortality in COVID-19 patients (83).

GABA treatment also enhanced IL-10 levels in SARS-CoV-2 infected mice. IL-10 is generally regarded as an anti-inflammatory cytokine, however, it can be immunostimulatory in certain contexts and elevated levels of IL-10 are associated with the development of severe COVID-19 (84, 85).

If the elevation of IL-10 levels in GABA-treated SARS-CoV-2 infected mice had counter-therapeutic effects, it is evident that GABA’s beneficial actions were functionally dominant leading to improved outcomes.

Conceivably, the enhanced levels of IL-10 levels due to GABA treatment may have been therapeutic by

1) its classical anti-inflammatory actions,

2) exhausting immune cells,

3) reducing tissue damage in the lungs, or

4) other yet to be identified actions.

Initiating GABA treatment 2-days after SARS-CoV-2 infection, near the peak of viral loads in the lungs, was essentially just as effective as initiating the treatment immediately post-infection in terms of limiting disease severity and death rates during the observation period.

Coinciding with those observations, the lungs of mice treated with GABA 2 days-post infection displayed reduced histopathological damage relative to untreated controls. It will be of interest to further test the efficacy of GABA when initiated at even later time points post-infection–however, the current findings clearly indicate GABA to be an excellent candidate therapeutic for COVD-19 and due to the inherent imperfections of any animal model, the ultimate test of this treatment will require human clinical trials.

Besides expressing the hACE2 transgene in lung cell epithelial cells, K18-hACE2 mice express hACE2 ectopically in their CNS leading to the spreading of SARS-CoV-2 infection to their CNS at late stages of the disease process (64, 66, 67). Because GABA does not pass through the blood-brain barrier (BBB), it is unlikely that GABA treatment directly exerted beneficial effects in the CNS.

However, the decreased levels of circulating proinflammatory cytokines and chemokines in GABA-treated mice may have also reduced their entry into the CNS. While SARS-CoV-2 is thought not to efficiently replicate in the human CNS (86), some COVID-19 patients experience cognitive impairments (or “brain fog”). Histological studies of the brains from COVID-19 patients have observed immune cell infiltrates and increased frequencies of glial cells with inflammatory phenotypes which are indicative of neuroinflammatory responses (86–93).

In previous studies, we have shown that treatment with homotaurine, a GABAA-R-specific agonist that can pass through the BBB, reduced the spreading of inflammatory T cell responses within the CNS, limited the pro-inflammatory activity of antigen-presenting cells, and ameliorated disease in mouse models of multiple sclerosis (15, 20).

Since microglia and astrocytes express GABAA-Rs which act to down-regulate their inflammatory activities (94), homotaurine treatment may have also limited glial inflammation. Homotaurine was as effective as GABA in protecting MHV-1-infected A/J mice from severe illness, pointing to GABAA-Rs as the major mediators of GABA’s beneficial effects in this model (54).

These observations suggest that homotaurine treatment may provide a new strategy to both reduce the deleterious effects of coronavirus infection in the periphery and limit inflammation in the CNS. Homotaurine (also known as Tramiprosate) was found to physically interfere with amyloid aggregation in vitro, leading to its testing as a treatment for Alzheimer’s disease in a large long-term phase III clinical study (95–97). While this treatment failed to meet primary endpoints, the treatment appeared to be very safe and follow-up studies suggested some disease-modifying effect (98, 99).

Finally, it is worth noting that circulating GABA levels are significantly reduced in hospitalized patients with COVID-19 (52, 53). This clinical finding, independent of our results presented here, raises the question of whether GABA therapy could be beneficial for COVID-19 patients.

It is likely that SARS-CoV-2 variants and novel coronaviruses will constantly arise that will be insufficiently controlled by available vaccines and antiviral medications. Developing new vaccines against these new viruses will be much slower than the spread of these new viruses among the world population.

Our findings suggest that GABA-R agonists may provide inexpensive off-the-shelf agents to help lessen the severity of disease caused by these new viruses. Because GABA’s mechanisms of action are unlike that of other coronavirus treatments, combination treatments could have enhanced benefits.

GABA is regarded as safe for human use and is available as a dietary supplement in the USA, China, Japan, and much of Europe (100). In other countries, because GABA is a non-protein amino acid, it is regulated as a medicinal agent or drug (e.g., in the UK, Canada, and Australia). In our studies, GABA at 2.0 and 0.2 mg/mL were equally effective at protecting SARS-CoV-2 infected mice from death (Figure 1B).

The human equivalent dose of GABA at 0.2 mg/mL [assuming consumption of 3.5 mL/day water, see Supplemental Figure 1 and calculated as per (101)] is 0.68 g/day for a 70 kg person, which is well within the level known to be safe (100). While our preclinical observations indicate that GABA-R agonists are promising candidates to help treat coronavirus infections, information on their dosing and the time window during which their effects might be beneficial or deleterious during a coronavirus infection in humans are lacking and clinical trials are needed to assess their therapeutic potential.


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