Research chemicalArylcyclohexylamine metaboliteAMPA modulatorInvestigational antidepressant

Hydroxynorketamine (2R,6R-HNK)

Also known as HNK · 2R,6R-hydroxynorketamine · (2R,6R)-HNK

Written by enwyReviewed 5 Aug 20262 sources0 comments

Hydroxynorketamine (HNK), specifically the 2R,6R enantiomer, is a major metabolite of ketamine that has drawn intense research interest as a possible antidepressant that works without NMDA blockade or dissociation. It remains preclinical/early-clinical and is not an approved drug, but is sold grey-market as a research chemical.

01 Overview

In rodent studies 2R,6R-HNK reproduces ketamine's rapid antidepressant-like effects apparently through AMPA receptor potentiation rather than NMDA antagonism, and without the dissociative, sedative or abuse-related effects. This made it a leading candidate for a non-dissociative rapid antidepressant.

Human data are minimal: early-phase trials have been conducted or planned, but efficacy in people is unproven. Its emergence as a research chemical means self-experimenters take it orally with essentially no human safety data, so its toxicology is uncharacterised.

02 Mechanism

Proposed AMPA receptor potentiation driving synaptic and BDNF/mTOR signalling; largely lacks the NMDA channel-blocking activity of the parent ketamine, hence little dissociation in animals.

03 Dosing

Tier	Dose	Route	Notes
No established human dose	0 mg	Oral	No validated human dosing; anecdotal RC use is unquantified and unsafe.

04 Effects

Effect	Magnitude	Evidence
Antidepressant-like effect (preclinical)Rapid, sustained antidepressant-like effects in animals without dissociation; unproven in humans.	rodent models	Preclinical
Minimal dissociationUnlike ketamine, little to no dissociative or sedative activity reported in animal work.	n/a	Preclinical

05 Side effects

Effect	Severity	Frequency	Evidence	Countermeasures
Unknown human toxicologyNo systematic human safety data; grey-market self-use carries unquantified risk.	Moderate	Unknown	Unconfirmed
Uncertain purityEnantiopurity and identity of grey-market material are unverifiable.	Moderate	Unknown	Unconfirmed

06 Legal status

United States

Not specifically scheduled; possible analogue exposure

As a ketamine metabolite/analogue it may fall under analogue provisions. · as of Jan 2026

United Kingdom

Likely captured by Psychoactive Substances Act 2016

Not a licensed medicine. · as of Jan 2026

07 References

NMDAR inhibition-independent antidepressant actions of ketamine metabolitesNature, 2016 (Zanos et al.)

(2R,6R)-hydroxynorketamine pharmacology reviewPharmacol Rev, 2018

08 Discussion0 comments

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This page is reference information, not medical advice. Doses and protocols are documented as they appear in the clinical literature and in practice — describing them is not a recommendation to use them. Countermeasures listed here are not a substitute for a physician. Legal status varies by jurisdiction and changes.