Arketamine and esketamine are the R(-) and S(+) enantiomers of ketamine, a compound that has been used for everything from anaesthesia and sedation to chronic pain and depression. Recently, esketamine as a nasal spray (Spravato™) made history as the first psychedelic-type substance approved by the U.S Food and Drug Administration (FDA) for treatment resistant depression.
Yet, ketamine’s often overlooked R(-) enantiomer may be both a more potent antidepressant and effect fewer perceptual disturbances than esketamine. Given the mixed results in the trials that led to esketamine’s approval, as well as the fact that suicide rates are at their highest level in the US since the end of World War 2, understanding the history, pharmacology, and therapeutic potential of arketamine could well be the key to helping millions regain control of their mental health and their lives.
Originally synthesized in 1962 by Calvin L. Stevens, a professor at Wayne State University and Parke-Davis consultant who was working on a series of phencyclidine derivatives, ketamine was first tested clinically on 20 volunteers at the Parke Davis Clinical Research Unit at Michigan’s Jackson Prison. Known at the time as CI-581, investigators found that intravenous infusion of ketamine produced a short acting and potent anesthesia with a low incidence of frank delirium. Subjects described “strange experiences like a feeling of floating in outer space and having no feeling in their arms or legs” and were observed to be disconnected with their immediate environment, leading it to be termed a “dissociate anesthetic”.
By the mid 1970s, however, as researchers like Stanislav Grof started studying ketamine’s potential as a tool for LSD-assisted psychotherapy, recreational use of ketamine had become very popular internationally. Often sold as an alternative to MDMA, ketamine has since enjoyed increasing popularity as a club drub, sometimes as part of a post-clubbing experience.
Unfortunately, as a result of its widespread use in unsupportive environments, as well as its subjective effects – dissociation, ataxia, immobilization, and more – ketamine has led to deaths all over the world, most often among young people and typically as a result of inadvertent poisoning (93 recorded deaths in UK between 2005-13) or other accident. Death from long-term abuse is less common, but has occurred, as in the case of Nancy Lee.
Ongoing concern with ketamine’s abuse potential has led to increased regulation around the world, with the US labelling it a Schedule III drug in 1999, and the UK upgrading it from Class C to B in 2014, citing “evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage”. It is worth noting that, although potential negative side effects exist, these appear to be confined to long term, frequent and inadequately monitored use.
Today, ketamine is often used off-label as a rapid-acting treatment for the most severe cases of depression (most often as an intravenous infusion). A single low, sub-anaesthetic dose of ketamine given via intravenous infusion appears to produce antidepressant effects within four hours, which then persist for up to several weeks. By contrast, other antidepressants, for example selective serotonin reuptake inhibitors and tricyclic antidepressants, generally take a least several weeks for benefits to become apparent. It is perhaps unsurprising then, that ketamine has been described as “arguably the most important discovery in half a century” in the treatment of depression.
Yet questions regarding safety and abuse potential persist for both ketamine and esketamine, meaning that it is all the more important to explore the potential of arketamine.
How does arketamine work – and is it safe?
Ketamine acts as a selective antagonist of the N-methyl-D-aspartate (NMDA) receptor (a glutamate and ion channel protein receptor), binding to the dizocilpine site as an uncompetitive antagonist). This activity is considered to be the cause of the anesthetic and hallucinogenic/dissociative effects associated with ketamine. Ketamine’s stereoisomers bind to the NMDA receptor with different affinities, with esketamine having nearly 2-3 times greater affinity than arketamine. Arketamine also shows 4 to 5 times lower affinity for the PCP site of the NMDA receptor. Finally, esketamine is 8 times more potent than arketamine as a dopamine reuptake inhibitor. As a result, arketamine shows lower potency than racemic ketamine and esketamine in terms of its perceptual disturbances.
As mentioned, although opinions on safety are still varied, ketamine — and by extension, its enantiomers — appears to be well tolerated when administered occasionally and at therapeutic doses. While arketamine appears to be safer and less liable to being abused than either ketamine or esketamine in animals, it will be critical to develop assess its efficacy, safety, and tolerability in patients with treatment-resistant depression.
There is good reason to be optimistic, however, as preclinical research has shown arketamine to be more effective as a rapid-acting anti-depressant than esketamine.
Arketamine belongs to a new generation of glutamate receptor modulators with the potential for rapid acting antidepressant (RAAD) activity and anti-suicidal effects. As mentioned, these new RAAD drugs are expected to be more efficacious than current FDA-approved anti-depressant therapies, which often take weeks to achieve maximal effectiveness, if at all. And while esketamine as a nasal spray has now been approved for treatment-resistant depression (Spravato™), its effectiveness appears limited; only two of five clinical trials showed statistically significant improvements in depressive symptoms. Notably, arketamine is anticipated to differentiate robustly from both ketamine and esketamine – as well as other development stage RAADs – both in terms of efficacy and safety.
In animal models of depression, the anti-depressant effects of arketamine appear to be greater in magnitude and longer-lasting than esketamine, while also producing no hyperlocomotion, deficits in prepulse inhibition, and maladaptive reward sensitivity, suggesting that arketamine should be both more effective for depression while carrying lower abuse potential in humans.
While the exact mechanisms are yet to be fully understood, different activities of arketamine and esketamine (as well as their metabolites) at the α7-nicotinic receptor have been suggested as the cause. Norketamine and hydroxynorketamine are potent antagonists at the α7-nicotinic receptor and markers of antidepressant effects are closely correlated with this affinity.
Indeed, it is now thought that Ketamine’s activity on the NMDA may not be responsible for its antidepressant effects.
It will be critical for Perception Neuroscience to conduct rigorous clinical trials to clearly establish arketamine’s therapeutic index in patients with treatment-resistant depression. Moreover, due to its effects on perception, esketamine – like ketamine – must be administered in a clinical setting under the supervision of a clinician, a process that may take multiple hours. This naturally limits the scaling potential of esketamine and may limit access to treatment.
Because of these limitations, it will be critical for Perception Neuroscience to demonstrate both arketamine’s efficacy and its lack of perceptual disturbances. Should that occur, it may be possible to provide arketamine on an outpatient basis, greatly improving its potential to alleviate the broader depression epidemic.