Phase 1 Results: Oral Ketamir-2 Safety and PK in Healthy Adults

Phase 1 Trial Finds Oral Ketamir-2 Safe and Well-Tolerated

Oral Ketamir-2, a novel selective N-methyl-D-aspartate (NMDA) receptor antagonist, demonstrated a favorable safety and tolerability profile in a first-in-human Phase 1 clinical trial (MIRA-001; OpenAlex W7214716908) conducted in 57 healthy adults. The randomized, double-blind, placebo-controlled study tested single and multiple ascending doses (50–600 mg) of Ketamir-2, finding no serious adverse events, no dose-dependent increase in adverse events, and no clinically meaningful dissociative or abuse-related effects. These results support the advancement of Ketamir-2 to Phase 2a studies for neuropathic pain.

Mechanism and Pharmacokinetics: A Non-Dissociative NMDA Antagonist

Ketamir-2 is designed as a low-affinity, phencyclidine-site-selective NMDA antagonist (IC50 ~100 µM), contrasting with ketamine’s high affinity and associated dissociative effects. The compound aims to retain analgesic activity while minimizing the risk of psychotomimetic or abuse-related side effects that limit ketamine’s clinical use. Pharmacokinetic analysis revealed rapid absorption (Tmax 1.0–2.5 hours), dose-dependent exposure, and no significant accumulation over five days of dosing. The major metabolite, Norketamir, exhibited dose-proportional exposure and a longer half-life (6.4–8.6 hours) compared to the parent compound (2.5–7.2 hours). Notably, exposures at 300 and 600 mg matched or exceeded levels associated with efficacy in preclinical neuropathy models, suggesting translational potential.

Implications for Pain Management and Psychoplastogen Development

The positive safety and pharmacokinetic profile of Ketamir-2 positions it as a promising candidate for neuropathic pain, a domain where oral ketamine’s poor bioavailability and dissociative side effects have constrained clinical adoption. If subsequent trials confirm efficacy, Ketamir-2 could expand the pipeline of orally available, non-dissociative NMDA antagonists, addressing an unmet need in pain management. More broadly, the development of selective, non-dissociative NMDA antagonists may inform the design of next-generation psychoplastogens—compounds that promote neural plasticity without the liabilities of classic psychedelics or dissociatives. A non-obvious implication is that regulatory agencies may view such agents more favorably for outpatient use, as the absence of acute psychoactive effects could simplify risk management and reduce barriers to prescription in primary care settings.

Risks, Limitations, and Unknowns

While Ketamir-2 was well-tolerated in healthy adults, several limitations and unknowns remain. The trial did not assess efficacy in pain or psychiatric populations, and the sample size (n=57) limits detection of rare adverse events. The absence of dissociative or abuse-related signals in short-term, controlled settings does not preclude such effects in broader or longer-term use. Additionally, the pharmacodynamic profile—how Ketamir-2 modulates pain or neuroplasticity in humans—remains to be established. Regulatory and payer acceptance will depend on robust evidence from Phase 2 and 3 trials, particularly regarding long-term safety and comparative effectiveness versus existing treatments. A real-world failure mode for novel NMDA antagonists is the emergence of subtle cognitive or mood effects not captured in early-phase trials, underscoring the need for careful monitoring as development progresses.

Next Steps: Advancing to Phase 2a and Beyond

The sponsor’s data support progression to Phase 2a trials in neuropathic pain, with dosing regimens informed by exposures shown to be safe and potentially efficacious. Future studies will need to evaluate not only analgesic efficacy but also the durability of effect, impact on quality of life, and real-world tolerability. Should Ketamir-2 demonstrate clinical benefit without dissociative or abuse liabilities, it may set a precedent for a new class of NMDA-targeting therapeutics in both pain and neuropsychiatric disorders. Researchers and clinicians should watch for trial registration and protocol details as the program advances. For stakeholders, the development of orally available, non-dissociative NMDA antagonists represents a concrete step toward safer, scalable interventions for chronic pain and possibly beyond.

Reviewed by Dr. Alex R. Green, MD, PhD (Clinical Pharmacology), on 2026-10-01. Research based on primary trial data and sponsor disclosures; see OpenAlex W7214716908 for original study.