Hydroxynorketamine

Pictured: Collage of woman on bed with ketamine pills/Taylor Tieden for BioSpace The week before Easter 2024, many of the world’s leading ketamine researchers gathered at the annual conference for ketamine and related compounds at the Blavatnik School of Government in Oxford. The first day ended with a debate about the suitability of at-home administration of ketamine for depression, preceded and followed by a vote from the audience. The vote before the debate was slightly opposed to using ketamine as a treatment for depression to be taken at home. However, after the exchange of expert opinions, the subsequent vote was slightly in favor. Though this apparent swing in the vote may reflect a minor change, the fact that the debate took place is itself noteworthy. It shows that the ketamine scientific community is actively working on how to ensure that the profound and fast-acting antidepressant properties of ketamine can benefit patients while its risks are mitigated. Depression is a growing health concern, affecting 320 million people worldwide, and it is expected to be the leading global cause of disease burden by 2030. Many depressed individuals do not respond adequately to current treatments, and about a third remain treatment-resistant after multiple treatment attempts. The emergence of ketamine-based medications has sparked hope for people with treatment-resistant depression because of the rapid onset of robust efficacy. However, that efficacy has so far generally occurred together with characteristic side effects such as dissociative psychological experiences and changes in heart rate and blood pressure. This has, in turn, prompted regulators to demand that the only approved ketamine-based medication for depression be taken under adequate medical supervision, effectively limiting its use. Ketabon, a Munich-based pharmaceutical company where I work as chief medical officer, is working to develop a medication that harnesses ketamine’s antidepressant effects without the safety issues that currently prohibit its at-home use. A Unique Mechanism To understand where the ketamine field stands today, it is of interest to look at the history of this groundbreaking medication. Calvin Stevens, a scientist at Parke-Davis Laboratories, synthesized the compound in 1962 while searching for new analgesics. Initially known as CI-581, ketamine quickly caught the attention of researchers, including Edward Domino, a pharmacologist at the University of Michigan who made a fortuitous observation: ketamine induced a unique dissociative state in human subjects, distinct from the experience under traditional anesthetics. This observation laid the groundwork for subsequent investigations into ketamine’s mechanism of action. Employing a combination of animal studies and pharmacological assays, Domino and his colleagues uncovered compelling evidence implicating the N-methyl-D-aspartate (NMDA) receptor—then an emerging player in the field of neuroscience—as the primary target of ketamine’s action. By antagonizing this receptor, ketamine disrupted glutamatergic neurotransmission, leading to its characteristic dissociative and anesthetic effects. One of the most significant advantages of ketamine is its ability to induce anesthesia rapidly and reliably, making it particularly well-suited for use in emergency settings or during procedures where rapid onset is essential. Additionally, it induces minimal respiratory depression compared with older anesthetics. However, ketamine is not without its limitations and potential drawbacks. Hallucinations, delirium and emergence phenomena can occur, particularly at higher doses or in susceptible individuals. Furthermore, concerns have been raised regarding its abuse potential and the development of tolerance and dependence with chronic use. When ketamine was used primarily in controlled settings as an anesthetic, the risk of diversion could be managed. The first inklings of ketamine’s abuse potential emerged in the late 1970s, as reports began to surface of individuals seeking out the drug for recreational purposes. Ketamine’s unique psychoactive effects captivated certain segments of the population, particularly within the burgeoning rave and club scene. From Anesthetic to Antidepressant While ketamine’s psychoactive effects raised the potential for abuse, some saw in them the potential for beneficial uses beyond anesthesia. In the late 1990s, intrigued by reports of ketamine’s rapid and robust impact on mood in patients undergoing anesthesia, John Krystal and his colleagues at Yale University embarked on a series of groundbreaking studies to explore its potential as an antidepressant. Their efforts bore fruit in 2000, when they published the first clinical trial demonstrating that a single sub-anesthetic dose of ketamine could produce rapid and sustained antidepressant effects in individuals with treatment-resistant depression. Subsequent research confirmed and expanded upon these findings, suggesting that ketamine’s antidepressant action was mediated by its ability to modulate the glutamatergic system in the brain, particularly through its antagonism of the NMDA receptor. Until that time, most efficacious antidepressants were acting by modulation of monoamine neurotransmission, particularly serotonin and noradrenaline signaling. Importantly, clinically relevant improvement could be seen within days of beginning ketamine treatment, rather than after several weeks as with standard antidepressants. Encouraged by these results, academic researchers and pharmaceutical companies raced to develop ketamine-based treatments for depression, paving the way for a diverse array of formulations and delivery methods, with intravenous infusion being frequently used. Among the most notable innovations was the development of Johnson & Johnson’s intranasal spray of esketamine, the S-enantiomer of ketamine, approved in 2019 and marketed under the brand name Spravato. It offers several advantages over traditional antidepressant medications, including a rapid onset of action and the potential to provide relief for individuals who have not responded to conventional therapies. But Spravato, too, is not without its limitations and caveats, including acute side effects such as dissociation and sedation, as well as the potential for abuse and misuse. The latter prompted regulatory agencies to impose strict risk mitigation strategies, including the requirement for administration under the supervision of a healthcare provider in a certified healthcare setting. Nevertheless, the introduction of Spravato represents a significant milestone in the treatment of depression. Several attempts have been made to strike a balance between efficacy benefits and tolerability issues with ketamine and related compounds and to safeguard against unintended use. Strict rules regarding who should administer the medication, where it can be administered and how patients must be supervised after each treatment, as in the case of Spravato, has been one approach. This has, however, limited accessibility to one of the most important antidepressant treatments. Abuse-deterrent formulations, use of small pack sizes and certification of pharmacies are examples of other approaches aiming to ensure the safe use of ketamine-based antidepressants. A fundamentally different approach is being pursued by Ketabon, where we are developing KET01, an oral prolonged-release form of ketamine administered as a tablet. Because of the slow uptake of ketamine from the gut and the extensive metabolism of ketamine in the liver, the amount of ketamine that reaches the general circulation is much lower than what is seen with ketamine-based medications administered intravenously, intranasally or with immediate-release tablets. The resulting low concentration of circulating ketamine is not sufficient to elicit characteristic side effects that are most likely mediated via the NMDA receptor, such as dissociation, sedation and blood pressure increase. However, due to the extensive metabolism of ketamine, relatively high concentrations of metabolites like norketamine and hydroxynorketamine are found in the circulation after dosing with KET01. These metabolites have shown antidepressant-like properties in animal models. Clinical trial data presented by Ketabon at recent meetings show a rapid improvement in depressive symptoms among patients with treatment-resistant depression receiving KET01, with maintenance of the improvement during the three-week treatment and four-week follow-up periods. These efficacy signals were not associated with increases in dissociation, heart rate or blood pressure. The researchers at Ketabon hypothesize that the antidepressant efficacy of KET01 is driven by ketamine metabolites, while the minimal dissociation can be attributed to the low levels of circulating ketamine. The emerging data with KET01 suggest that it is indeed possible to achieve rapid improvement in depression without the characteristic side effects of ketamine-based medications. This raises the potential for broader and safe use of a ketamine-based medication for depression, with an improved tolerability profile. If this treatment is eventually approved, it will be interesting to see how its availability would affect the results of a vote regarding home use of ketamine like the one recently held at Oxford. Hans Eriksson, MD, PhD, MBA, is chief medical officer at Ketabon and HMNC Brain Health in Munich. Follow him on LinkedIn or learn more about his work at and .