2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health - LARVOL DELTA

Long-lasting analgesic effects of (2R,6R)-Hydroxynorketamine in a chemotherapy-induced peripheral neuropathy mouse model. (Neuroscience 2025) - "There are no approved drugs for treating the neuropathy, with duloxetine providing limited benefits. (2R,6R)-HNK produced long-lasting analgesic effects in a CIPN mouse model without tolerance that persisted following treatment cessation. Pharmacological experiments point to the involvement of AMPA, as well as mGLUR2 and mGLUR2/3 receptors in (2R,6R)-HNK-induced analgesia. Opioid receptors appear to have no involvement, since naltrexone failed to block these effects."

Preclinical • CNS Disorders • Pain • Peripheral Neuropathic Pain

TREK-1 Channel Blockade Mediates the Antidepressant-like Effects of Hydroxynorketamine. (PubMed, Neuropharmacology) - "Crucially, the antidepressant effects of (2R,6R)-HNK were abolished in mice with pyramidal neuron-specific knockdown of TREK-1 in the mPFC, confirming the essential role of TREK-1 inhibition in mediating (2R,6R)-HNK's actions. Our findings establish TREK-1 as a critical target for (2R,6R)-HNK's rapid antidepressant effects, providing new insights into the mechanisms of depression treatment and the development of novel therapeutics."

Journal • CNS Disorders • Depression • Psychiatry • DLG4

COMPARISON OF (2R,6R)-HYDROXYNORKETAMINE, PREGABALIN AND MORPHINE ON MOTOR COORDINATION AND THERMAL ANALGESIA IN NAÏVE MICE (ASA 2025) - "Mean tail flick responses before drug administration were 2.3±0.9 s. The %MPE was 37±26 s for RR-HNK, 30±8s for pregabalin and 46±10 for morphine. The antinociceptive effect of pregabalin 30mg/kg was less than morphine 5mg/kg, but there were no differences among morphine 5mg/kg, pregabalin 100mg/kg or (2R,6R)-HNK 30mg/kg. All morphine and RR-HNK animals were able to maintain motor coordination for 300 s at 30 min following tail flick testing."

Preclinical • Addiction (Opioid and Alcohol) • Anesthesia • Immunology • Musculoskeletal Pain • Otorhinolaryngology • Pain • Vertigo

The effects of low-dose ketamine and (2R,6R)-Hydroxynorketamine on affective behaviors associated with protracted oxycodone withdrawal. (PubMed, Psychopharmacology (Berl)) - "These findings demonstrate the therapeutic potential of (2R,6R)-HNK and ketamine in alleviating affective symptoms of oxycodone withdrawal."

Journal • Substance Abuse

(2R,6R)-hydroxynorketamine reverses mechanical and thermal pain hypersensitivity produced by the chemotherapeutic agent oxaliplatin in rats. (PubMed, J Pharmacol Sci) - "In comparison, repeated duloxetine (15 mg/kg/day, s.c.) showed only a short-lasting reduction of thermal hypersensitivity and no effect on mechanical hypersensitivity. This is the first demonstration that (2R,6R)-HNK produced analgesia in a rat model of CIPN. The persistence of analgesia with repeated treatment and sustained effects following treatment cessation suggests that (2R,6R)-HNK may represent a promising new therapeutic strategy for the rapid and sustained relief of pain associated with CIPN."

Journal • Preclinical • Immunology • Neuralgia • Oncology • Pain • Peripheral Neuropathic Pain

Development and Validation of a Rapid LC-MS/MS Method for Plasma Analysis of Ketamine, Norketamine, Dehydronorketamine, and Hydroxynorketamine. (PubMed, Biomed Chromatogr) - "Using positive electrospray ionization, linear quantification ranges of 1-1,000 ng/mL were established for ketamine and norketamine, while ranges of 0.25-100 ng/mL for DHNK and 2.5-1,000 ng/mL for (2R,6R)-HNK were achieved...Overall, this LC-MS/MS method offers a robust and efficient approach for the achiral quantification of ketamine and its metabolites in human plasma. Its minimal sample preparation and reduced analytical runtime make it particularly well-suited for clinical studies, drug monitoring, and forensic investigations."

Journal • Anesthesia • CNS Disorders • Depression • Psychiatry

Behavioral and biochemical changes associated with the analgesic effects of (2R,6R)-hydroxynorketamine alone and in combination with meloxicam following disk puncture in mice. (PubMed, Front Pain Res (Lausanne)) - "Our findings demonstrated that the analgesic benefit of (2R,6R)-Hydroxynorketamine is dose dependent, protein analysis suggests that (2R,6R)-HNK analgesic is associated with augmenting GluA1, GluA2, CaMKII, Kv2.1 and a reduction in BDNF protein ratios in hippocampus, decreased spinal cord c-Fos and reduced BNDF at the dorsal root ganglion. (2R,6R)-Hydroxynorketamine also augmented meloxicam analgesia in disk puncture mice. Our finding supports further study of the clinical potential of (2R,6R)-Hydroxynorketamine as a non-opioid analgesic for discogenic back pain."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Back Pain • Lumbar Back Pain • Musculoskeletal Diseases • Musculoskeletal Pain • Pain • BDNF • FOS

Bioactive ketamine metabolite exerts in vivo neuroplastogenic effects to improve hippocampal function in a treatment-resistant depression model. (PubMed, Cell Rep) - "Prior experience with spatial learning partially occluded LTP in control rats, an effect mimicked in LTP-impaired rats in which spatial learning deficits were reversed by (2R,6R)-HNK. These findings demonstrate that (2R,6R)-HNK exerts rapid neuroplastogenic effects in vivo, which improve cognitive function and promote adaptive changes in synaptic strength at functionally impaired synapses."

Journal • Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry

The antidepressant potential of (2R,6R)-hydroxynorketamine: A detailed review of pre-clinical findings. (PubMed, Eur J Pharmacol) - "In conclusion, (2R,6R)-HNK shows promise as a next-generation antidepressant. However, further research is needed to fully understand its long-term safety and mechanisms, and to determine its advantages over existing treatments like esketamine, particularly for TRD patients."

Journal • Preclinical • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry

(2R,6R)-hydroxynorketamine prevents opioid abstinence-related negative affect and stress-induced reinstatement in mice. (PubMed, Br J Pharmacol) - "These findings emphasize the therapeutic potential of (2R,6R)-HNK, which is currently in Phase II clinical trials, in addressing stress-related opioid responses. Reducing the time and cost required for development of new medications for the treatment of OUDs via drug repurposing is critical due to the opioid crisis we currently face."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Mood Disorders • Psychiatry • Substance Abuse • GRIN2A

Investigation of the Antidepressant Effects of (2R,6R)-HNK, an Enhancer of Synaptic Glutamate Release, in Treatment-Resistant Depression (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: National Institute of Mental Health (NIMH) | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

Effect Of (2r,6r)-Hydroxynorketamine On C-Fos Expression In A Murine Model Of Back Pain (ASA 2024) - "The DP model of low back pain has been shown to be associated with mechanical allodynia and upregulation of proteins involved with pain pathways in the hippocampus. In the current study we observed upregulation of the expression of c-fos in the spinal cord of DP mice compared with (2R,6R)-HNK or sham controls. It has been shown that c-fos, through its protein form, FOS, leads to expression of dynorphin gene and subsequently dynorphin protein."

Preclinical • Back Pain • Lumbar Back Pain • Musculoskeletal Pain • Pain • FOS

Evaluation Of The Analgesic Activity Of Co-Administration Of (2r,6r)-Hydroxynorketamine With Meloxicam In Murine Model Of Low Back Pain (ASA 2024) - "Baseline median paw withdrawal pressure (PWT) to von Frey stimulation were 3.69 (95% CI 3.17 to 3.69) grams. Fourteen and twenty-one days after surgery, median PWT values were 0.77 grams (95% CI 0.40 to 0.65) and 0.47 (95% CI 0.43 to 0.60) and were not significant among treatment groups. Meloxicam, (2R,6R)-HNK 10 mg & 20mg and the combinations of meloxicam and (2R,6R)-HNK all increase the AUC greater than saline (P<0.05) (Figure)."

Preclinical • Back Pain • Lumbar Back Pain • Musculoskeletal Diseases • Musculoskeletal Pain • Pain

Evaluation Of (2r,6r)-Hydroxynorketamine Ed50 And Peripheral Activity In The Dorsal Root Ganglia In A Murine Model Of Low Back Pain (ASA 2024) - "The large difference in ED50 antiallodynic dose in male mice (10.7 mg/kg) versus female mice (22.5 mg/kg) indicates a sex dependent difference in response. There were no significant changes in the ratios of TRPA1, TrkB, p-ERK, and BDNF to GAPDH in the dorsal root ganglia, suggesting no peripheral modulation of the pain pathway. This finding in the DRG coupled with previous findings in the hippocampus suggest that (2R,6R)-HNK is a primarily centrally acting modulator."

Preclinical • Addiction (Opioid and Alcohol) • Back Pain • Lumbar Back Pain • Musculoskeletal Pain • Pain • BDNF • GAPDH • NTRK2 • TRPA1

(2R,6R)-hydroxynorketamine alleviates PTSD-like endophenotypes by regulating the PI3K/AKT signaling pathway in rats. (PubMed, Pharmacol Biochem Behav) - "Traumatic stress can trigger negative emotional reactions in rats, potentially involving the PI3K/AKT signaling pathway in the HIP, PFC, and AMY. The (2R, 6R)-HNK compounds have demonstrated the potential to mitigate adverse emotions in rats subjected to the SPS&S paradigm. This effect may be attributed to the modulation of the PI3K/AKT signaling pathway in the HIP, and PFC, with a particularly notable impact observed in the HIP region."

Journal • Preclinical • CNS Disorders • Depression • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry • Suicidal Ideation • AKT1

Exploring ketamine's potential in treating Alzheimer's disease (ECNP 2024) - "The potential of ketamine to treat depression in AD patients has been assessed through neurocognitive performance measures, imaging, and clinical evaluations.However, ketamine's side effects, including neurotoxicity and dissociation, necessitate careful dosing and the exploration of alternative formulations, such as (R)-ketamine and (2R,6R)-HNK, which may offer similar benefits with fewer side effects. Animal studies demonstrate that low-dose ketamine enhances cognitive function without inducing adverse behavioral effects. In human trials for depression, ketamine has shown the potential to improve cognitive tasks, suggesting possible benefits for AD patients. Ketamine and memantine, despite having similar pharmacological profiles, exhibit key differences in their effects."

Alzheimer's Disease • CNS Disorders • Depression • Psychiatry • BDNF

Reduction in ethanol consumption in mice following (2R,6R)-Hydroxynorketamine (Neuroscience 2024) - "There was an overall treatment effect of (2R,6R)-HNK, reducing ethanol consumption by approximately 10% in both male and female mice, during the treatment week and the week following treatment cessation, indicative of sustained action of the drug. In conclusion, (2R,6R)-HNK may be a novel therapeutic for AUD."

Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Pain

(2R, 6R)-hydroxynorketamine ameliorates PTSD-like behaviors during the reconsolidation phase of fear memory in rats by modulating the VGF/BDNF/GluA1 signaling pathway in the hippocampus. (PubMed, Behav Brain Res) - "(2R,6R)-HNK modulates the VGF/BDNF/GluA1 signaling pathway in the hippocampus and improves PTSD-like behaviors during the reconsolidation phase of fear memory in rats, which may provide a new target for the clinical treatment and prevention of fear-related disorders such as PTSD."

Journal • Preclinical • CNS Disorders • Depression • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Ketamine and major ketamine metabolites function as allosteric modulators of opioid receptors. (PubMed, Mol Pharmacol) - "All three opioid receptors (mu, delta, and kappa) showed synergism with submicromolar concentrations of ketamine and either Met-enkephalin, Leu-enkephalin, and/or dynorphin A17, albeit the extent of synergy was variable between receptors and peptides...Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at mu opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors...Significance Statement We found that ketamine and its major biologically-active metabolites function as potent allosteric modulators of mu, delta, and kappa opioid receptors, with submicromolar concentrations of these compounds synergizing with endogenous opioid peptides such as enkephalin and dynorphin. This allosteric activity may contribute to ketamine's therapeutic effectiveness for treating acute and chronic pain and as a fast-acting antidepressant drug."

Journal • Anesthesia • Pain • PENK

Synthesis of small molecule haptens for vaccination against psychoactive mixtures: Deconvoluting the mechanisms of action of ketamine and psychedelic tryptamines (ACS-Fall 2024) - "Small molecule haptens for ketamine, norketamine, and 6-hydroxynorketamine were synthesized and conjugated to a carrier protein to produce an antigen, whose immune responses were assessed via ELISA and SPR. We additionally are synthesizing haptens targeting different tryptamine compounds to compare the antibodies’ cross-reactivity with various tryptamine analogues and assess their individual abilities to serve as a reversal agent for multiple analogues and, when used in tandem, their capability to distinguish structural differences and thus detect cryptic tryptamine analogues."

Anesthesia • CNS Disorders • Mental Retardation • Psychiatry

Investigation of the Antidepressant Effects of (2R,6R)-HNK, an Enhancer of Synaptic Glutamate Release, in Treatment-Resistant Depression (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: National Institute of Mental Health (NIMH)

New P2 trial • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions. (PubMed, Neuropharmacology) - "A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients."

Journal • Anesthesia • CNS Disorders • Depression • Mood Disorders • Psychiatry

Effects of (2R,6R)-hydroxynorketamine in assays of acute pain-stimulated and pain-depressed behaviors in mice. (PubMed, PLoS One) - "The positive controls morphine (hot plate test) and ketoprofen (acetic acid writhing, locomotor activity, and rearing) blocked pain-stimulated and pain-depressed behaviors. Intermittent administration of (2R,6R)-HNK also did not produce antinociceptive effects in the hot plate or pain-depressed locomotor activity assays. These results suggest that (2R,6R)-HNK is unlikely to have efficacy in treating acute pain; however, the efficacy of (2R,6R)-HNK in chronic pain states should continue to be evaluated."

Journal • Preclinical • CNS Disorders • Depression • Pain • Psychiatry

The Development of Ketamine for Depression: A Long and Winding Road from Inception to Implementation (SOBP 2024) - "Intranasally-administered esketamine (ketamine’s S-enantiomer) is FDA-approved in adults for treatment-resistant depression and for major depressive disorder with acute suicidal ideation. I will also discuss the NIH multi-institutional effort to explore the antidepressant effects of (2R,6R)-hydroxynorketamine (HNK), a ketamine metabolite. A Phase 2 trial of (2R,6R)-HNK—which is not an anesthetic, has no dissociative side effects, and no misuse potential—will begin at the NIMH in the next few months."

CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • Suicidal Ideation

Ipsc-Derived Neurons from Depressed and Healthy Participants Display Diagnostic- And Treatment-Dependent Differential Gene Expression (SOBP 2024) - "Samples were treated with (2R,6R)-HNK (0.25-1uM), ketamine (1uM), DOI (10uM), LSD (10uM), and Psilocybin (1, 10uM), collected for RNA-sequencing and assessed through DeSeq2 and GO-BP. Significant diagnostic differences were found in transmembrane transporter activity, growth factor binding, and glutamate receptor activity (padj<0.01). After treatment with HNK (all doses), forebrain cell migration and neuron development pathways were affected (padj<0.0001). Treatment with serotonergic psychedelics enriched pathways related to cilium organization, axonogenesis, and protein localization (padj<0.0001 for DOI, Psilocybin, and LSD)."

Clinical • Late-breaking abstract • CNS Disorders • Depression • Psychiatry