AniracetamvsPhenibut

Aniracetam is a positive allosteric modulator of AMPA receptors, binding to the allosteric site and slowing receptor desensitization, which prolongs excitatory postsynaptic currents and facilitates long-term potentiation. It also modulates group II metabotropic glutamate receptors (mGluR2/mGluR3), which regulate presynaptic glutamate release. Uniquely among racetams, aniracetam increases dopamine and serotonin release in the prefrontal cortex via modulation of monoamine transporter activity and vesicular release, contributing to its anxiolytic and mood-enhancing effects. It reduces GABAergic inhibition in the hippocampus through indirect modulation of GABA-A receptors, facilitating NMDA receptor activation and memory consolidation. The lipophilic phenylacetyl group enables rapid blood-brain barrier penetration.

Phenibut is a structural analog of GABA with a phenyl ring that confers lipophilicity and allows blood-brain barrier penetration (unlike GABA itself). It acts as a GABA-B receptor agonist, binding to the GABAB1/GABAB2 heterodimer and activating Gi/o-coupled signaling (similar to baclofen), producing anxiolytic, muscle relaxant, and sedative effects through inhibition of adenylyl cyclase and modulation of potassium and calcium channels. Phenibut also blocks the alpha-2-delta-1 and alpha-2-delta-2 subunits of voltage-gated calcium channels, reducing presynaptic calcium influx and neurotransmitter release (similar to gabapentin/pregabalin). The dual mechanism—GABA-B agonism dampening inhibitory interneurons and calcium channel blockade reducing excitatory transmission—produces potent anti-anxiety and sleep-promoting effects. Rapid tolerance develops due to receptor downregulation.