# Hydroxynorketamine for the Treatment of PTSD and Anhedonia

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2021 · —

## Abstract

Deleterious psychiatric outcomes following stress afflict many recently deployed combat Veterans.
Recent evidence has shown that low doses of the anesthetic ketamine rapidly ameliorate depression,
posttraumatic stress disorder (PTSD), anhedonia (a reduced capacity to experience pleasure), and suicidality
within hours following a single administration. These effects extend to treatment-resistant populations,
implicating ketamine as a novel and unique pharmacological option for treating psychiatric illnesses that
disproportionately impact our combat Veterans. Despite these promising results, ketamine's use as a treatment
outside of a hospital or clinic setting is limited due to its capacity to produce dissociative effects even at low
doses and abuse liability.
 Ketamine's anesthetic effects are likely mediated by inhibition of the NMDA glutamate receptor
(NMDAR) and as a consequence all of the drug's psychiatric effects (both negative and therapeutic), were
assumed to have a similar underlying mechanism of action. Ketamine is rapidly metabolized into a number of
metabolites, including hydroxynorketamines (HNKs) that are much less potent inhibitors of the NMDAR. We
recently demonstrated (Nature, 2016) that the (2R,6R)-HNK metabolite exerts actions identical to ketamine in
preclinical tests predictive of rapid and sustained antidepressant efficacy. Of significance, we found that even
very high doses of (2R,6R)-HNK lack anesthetic and dissociative effects, as well as abuse liability in preclinical
tests. Our goal is to develop an improved intervention for the treatment of stress-related disorders in Veterans,
given what we know of ketamine's relevant pharmacological actions.
 Our preliminary data indicates that the (2R,6R)-HNK metabolite that is produced in humans after
ketamine administration, may be an ideal treatment for PTSD and anhedonia afflicting Veterans exposed to
stress. In Specific Aim #1, we will define the actions of ketamine compared to (2R,6R)-HNK in mouse tests of
PTSD domains including conditioned fear responses and fear extinction, hyperarousal measured by acoustic
startle responses, and electroencephalogram sleep abnormalities, both under control conditions and following
stress. We will test effects of both pre- and post- symptom administration, predicting that (2R,6R)-HNK will be
necessary and sufficient to exert the therapeutic effects of ketamine on different domains/endophenotypes
associated with PTSD. In Specific Aim #2, we will determine actions of ketamine and its (2R,6R)-HNK
metabolite on consummatory, anticipatory, and motivational subtypes of anhedonia, which has relevance to
anhedonia observed as a symptom in patients with PTSD; as well as those with depression, schizophrenia,
Parkinson's, and Alzheimer's disease.
 We anticipate that (2R,6R)-HNK will prove efficacious in several important experimental measures, and
that successful completion of the project will provide the preclinical evidence that is needed for (2R,6R)-H...

## Key facts

- **NIH application ID:** 10046271
- **Project number:** 5I01BX004062-03
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Todd D Gould
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046271

## Citation

> US National Institutes of Health, RePORTER application 10046271, Hydroxynorketamine for the Treatment of PTSD and Anhedonia (5I01BX004062-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10046271. Licensed CC0.

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