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AV-101 is an oral prodrug, not an active drug in the blood; once it crosses into the brain, astrocytes convert it into 7-chlorokynurenic acid, a potent blocker of the glycine co-agonist site on the NMDA receptor. The pitch from VistaGen Therapeutics was a ketamine-like antidepressant you could take as a pill with none of the dissociation, since the parent compound itself does nothing until it's converted locally in brain tissue. Early studies, including a neurophysiology trial in veterans, confirmed it does engage NMDA receptor signaling in humans exactly as designed. But the pivotal Phase II depression trial did not separate from placebo, and VistaGen shifted its psychiatric pipeline toward other candidates, leaving AV-101 as a mechanistically elegant idea that worked at the target but not at the endpoint.
- oral dosing (no infusion required)
- confirmed NMDA target engagement in EEG/neurophysiology studies
- no dissociation reported at tested doses
- clean early safety profile
- no clear antidepressant separation from placebo in Phase II
- AV-101 does nothing on its own; it has to be converted by astrocytes into 7-chlorokynurenic acid before it can touch the NMDA receptor at all.
- A crossover neurophysiology study in military veterans used EEG signatures of NMDA blockade to confirm AV-101 was hitting its target in living human brains, even though the depression trial itself came up short.
Mechanism
Oral converted in the brain (via astrocytes) to 7-chlorokynurenic acid, a selective at the glycine co- site of the ; also modulates release via alpha7 receptors.
Safetyrisks and cautions, not medical advice
Eighty-six healthy volunteers took AV-101 across two Phase 1 studies, up to 1,440 mg a day for fourteen days, and the adverse events were indistinguishable from placebo in both kind and frequency, with nothing flagged on electrocardiograms, eye examinations or neurocognitive testing. A later crossover study in veterans at the same top dose was likewise uneventful, and there was no dissociation, which is the whole point of blocking the glycine site instead of the channel. Exposure longer than a couple of weeks has not been studied.
History
Developed by VistaGen Therapeutics, building on earlier NIH/academic kynurenine-pathway research; reached Phase I safety/PK studies and a Phase II trial in major depressive disorder in the mid-to-late 2010s; discontinued for depression after the pivotal trial missed its primary endpoint.
Subjective profileweighing the evidence above
A genuinely clever delivery trick, an oral drug that only becomes an NMDA blocker once inside the brain, that confirmed target engagement but not clinical benefit.
Resources
This entry is here for reference.
Research
- 1.Randomized, double-blind, placebo-controlled, dose-escalation study: Investigation of the safety, pharmacokinetics, and antihyperalgesic activity of l-4-chlorokynurenine in healthy volunteers
- 2.A randomized cross-over trial to define neurophysiological correlates of AV-101 N-methyl-D-aspartate receptor blockade in healthy veterans
2 listed here; entry last updated July 2026
Reviews
My notesprivate to this device
FAQ
Is AV-101 the same as ketamine?
No. It targets the glycine co-agonist site of the NMDA receptor rather than blocking the channel pore directly, and it's an oral prodrug rather than an infusion.
Why did VistaGen stop developing it for depression?
Its pivotal Phase II trial in major depressive disorder did not beat placebo on the primary endpoint, even though earlier studies showed it engaged the intended NMDA target in the brain.
Limitations of the evidence
- limited long-term human data
Adverse effects
- no clear antidepressant separation from placebo in Phase II