Psychedelic substances such as psilocybin, LSD, DMT, and mescaline have drawn attention from neuroscientists, clinicians, and the public for their profound effects on human consciousness, emotion, and perception [1]. This interest has only increased in the years since the global pandemic [2].
Much of the research has focused on the modulating effect of psychedelics on the serotonergic system, particularly the 5-HT2A receptor [3]. However, recent evidence has suggested that psychedelics may also influence the gamma-aminobutyric acid (GABA) system [4,5]. This is an inhibitory neurotransmitter network that is crucial for neural balance, regulating anxiety, and orchestrating states of consciousness such as sleep and wakefulness.
In this article, we explore the emerging evidence around how psychedelics interact with the GABA system, both directly and indirectly, and what implications this might have for mental health and therapeutic applications.
The GABAergic system: How does it work?
GABA is the brain’s main inhibitory neurotransmitter [6,7]. This means that it plays a critical role in blunting neural excitability, stabilizing brain activity, and promoting relaxation.
Errors or dysregulation in GABAergic signaling are linked with anxiety, depression, schizophrenia, and epilepsy, to name a few [8,9]. Considering the central role of GABA in balancing excitatory neurotransmission, it’s important to appreciate how psychedelics might influence this important system.
Classic psychedelics and their mechanism of action
Many of the classical psychedelics that people have heard of, such as psilocybin, LSD, DMT, and mescaline, act on the 5-HT2A receptor. They exert their psychoactive effects by acting as agonists or partial agonists on this receptor, which is heavily expressed in cortical areas of the brain that influence cognition, emotions, memory, and perception [10,11].
Activation of 5-HT2A receptors leads to enhanced glutamate release and increased cortical excitation, which underlies the characteristic perceptual and cognitive alterations induced by psychedelics.
However, this cortical excitation does not occur in isolation. Neuronal networks are dynamically regulated by a balance between excitatory (glutamatergic) and inhibitory (GABAergic) signals. As such, the interaction between serotonergic modulation and GABAergic regulation is an area of growing interest.
Psychedelics and GABA: Psilocybin, psilocin, and indirect crosstalk via serotonin
While psychedelics do not bind strongly to GABA receptors themselves, they can indirectly influence GABAergic tone through their effects on the serotonergic system, particularly through 5-HT2A and 5-HT1A receptors [12,13].
Psilocybin and psilocin may regulate cortical microcircuits by activating 5-HT2A receptors expressing GABAergic interneurons and increasing GABA release in the prefrontal cortex (PFC) [13].
Psilocybin also appears to regulate long-range cortical-subcortical circuits by rapidly increasing GABA release in the thalamus and increasing GABA levels in the PFC after 140 minutes of administration [5].
In contrast to 5-HT2A receptors, activation of 5-HT1A receptors, which psychedelics also bind to with varying affinity, can have anti-anxiety and inhibitory effects, partially mediated by enhancing GABAergic activity [14-16]. In the raphe nuclei, 5-HT1A receptor activation leads to decreased serotonin release, which may downregulate excitation in downstream cortical areas in the brain.
This dual action (excitatory via 5-HT2A and inhibitory via 5-HT1A) represents a complex push-pull relationship, with the specific balance likely depending on the psychedelic compound, dose, receptor binding affinity, and individual neurobiology.
Evidence from neuroimaging and electrophysiology studies
Combined evidence from neuroimaging and electrophysiology studies indirectly points to the interaction between psychedelics and the GABA system. These studies have utilized EEG methods, magnetic resonance spectroscopy, and resting-state fMRI techniques to highlight these interactions [17-19].
The role of GABA in the therapeutic effects of psychedelics
Psychedelics show promise for treating mental health conditions like depression, anxiety, PTSD, and addiction [20,21]. Given that GABA deficits are commonly observed in these disorders [9], the interaction between psychedelics and GABA may play a critical role in their potential therapeutic effects.
Patients with major depressive disorder often exhibit reduced GABA levels in the brain [22]. Psychedelics may help normalize inhibitory-excitatory balance through a transient reduction of GABAergic tone, followed by neuroplastic adaptation and restoration of healthy network function. Some theorize that this disruption-reintegration process may be key to the therapeutic reset observed in psychedelic therapy.
GABAergic circuits are also essential for regulating the amygdala and limbic system. By modulating these inhibitory networks, either directly or via serotonergic intermediaries, psychedelics may alleviate anxiety and fear responses [23], especially when combined with psychological support.
Conclusion
Although classic psychedelics primarily target serotonergic receptors, their indirect influence on the GABAergic system is both biologically plausible and increasingly supported by research evidence. It seems that psychedelics reduce GABAergic inhibition in certain cortical circuits, particularly via 5-HT2A receptors, but also 5-HT1A. Psychedelics show promise for helping to treat mental health conditions, with GABA representing an indirect mechanistic pathway.
Future research will likely explore how individual differences in GABAergic tone influence response to psychedelics and whether co-therapies targeting GABA (e.g., benzodiazepines or GABA agonists) might enhance or interfere with psychedelic therapy.
As the field moves forward, a systems-level understanding of how GABAergic and serotonergic networks interact will be paramount for optimizing psychedelic therapies and mitigating any risks.
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