Ketamine, a mixture of two mirror-image molecules called (S)-ketamine and (R)-ketamine, is used as an anesthetic and, more recently, as an antidepressant, but it carries a risk of abuse. The (S)-form is FDA-approved for treatment-resistant depression, while the (R)-form shows promise in animal models but has not been tested in people. In rats and mice, (S)-ketamine, but not (R)-ketamine, produced behaviors linked to abuse potential, such as self-administration, increased movement, and preference for places where the drug was given. (S)-ketamine also boosted activity and dopamine levels in a brain region called the medial prefrontal cortex, partly by activating opioid receptors. These findings indicate that the abuse liability of racemic ketamine stems mainly from its (S)-enantiomer.
Ketamine, an anesthetic, produces rapid antidepressant effects in people with treatment-resistant depression when given at sub-anesthetic doses, leading to FDA approval of esketamine. The mechanisms behind these effects remain under investigation, with evidence suggesting that ketamine's metabolites, such as (2R,6R)-hydroxynorketamine (HNK), may play a key role. HNK shows antidepressant potential in preclinical tests without ketamine's dissociative or abuse-related side effects. The review discusses how ketamine and its metabolites influence glutamate signaling through NMDARs and AMPARs, synaptic changes via BDNF, opioid receptor interactions, and enhancement of serotonin, norepinephrine, and dopamine signaling. Targeting these pathways could yield new rapid-acting antidepressants with fewer side effects.