Many people interested in our treatments ask us about the differences and similarities between ketamine and esketamine. Although they share pharmacological roots and both have proven their value in the treatment of various mental disorders, including treatment-resistant depression, there are known to be important differences in formulation, administration, and side-effect profiles.
Both compounds act on glutamate receptors in the brain but differ subtly in some of their precise mechanisms. It is essential that patients and healthcare professionals are well informed about these distinctions to make informed decisions in the design of personalized treatments.
Ketamine is a drug that has been used for more than five decades mainly as an anesthetic but has also shown interesting effects as a line of intervention for treatment-resistant depression and other psychiatric disorders administered in different ways. Ketamine exists in two stereoisomeric forms: the R-ketamine form and the S-ketamine (esketamine) form. This means that they have the same molecular formula but differ in how their atoms are arranged in three-dimensional space.
Ketamine is a medication that has been used for more than five decades mainly as an anesthetic, but it has also shown interesting effects as a line of intervention for treatment-resistant depression and other psychiatric disorders administered in different ways. Ketamine exists in two stereoisomeric forms: the R-ketamine form and the S-ketamine (esketamine) form. Which means they have the same molecular formula, but differ in how their atoms are arranged in three-dimensional space. The ketamine synthesized in 1962 by Calvin Stevens, called racemic ketamine, is composed of a mixture of the two stereoisomeric forms, and is what we use in our clinic. It has the greatest evidence of its effectiveness in the treatment of treatment-resistant depression given its long history of use.
Thus, S- Ketamine (esketamine) is said to have a higher affinity for NMDA (N-methyl-D-aspartate) receptors, which could mean it has a higher analgesic and anaesthetic potency than the racemic ketamine mixture.
Studies show that these differences are crucial in assessing the suitability of both for the treatment of treatment-resistant depression. A first study in 2015 in adult mice compared the antidepressant effects of ketamine stereoisomers (R and S) in models of social defeat stress depression and learned helplessness. This research revealed differences at different levels: mechanism of action, side effects, outcome improvement and duration of effects. On the one hand, mice given S-ketamine (esketamine), but not R-ketamine, showed increased hyperactivity as a side effect. On the other hand, when it came to restoring their ability to experience pleasure, interest or satisfaction, (R)-ketamine was significantly more potent than (S)-ketamine, which is of particular interest for depressed patients with anhedonia. The effects were also longer lasting in the R-ketamine than in the S-ketamine subjects.
Another study mentions that S-ketamine has approximately four times higher affinity for the NMDA receptor than (R)-ketamine, so the anaesthetic effects may be stronger with (S)-ketamine (esketamine). The study also showed a significant decrease in the ability of dopamine receptors to bind dopamine in the striatum following a dose of (S)-ketamine (but not (R)-ketamine), implying an increase in dopamine in the synaptic space). This may be a consequence of possible acute psychotomimetic and dissociative side effects in humans.
Based on the results of previous research, although rigorous research is still needed, both racemic ketamina and (R)-ketamine may have a safer antidepressant effect than (S)-ketamine. These results have been replicated in several clinical trials, although all versions of ketamine have shown good results.
Regarding subjective effects, both racemic ketamine and esketamine have greater dissociative or psychedelic effects than R-ketamine alone. At anesthetic doses, esketamine appears to show more pleasant effects, with less lethargy, acute cognitive impact, and fatigue upon awakening. However, at subanesthetic doses there is a higher percentage of unpleasant experiences with esketamine than with racemic ketamine, suggesting that the mixture with R-ketamine helps provide a more pleasant psychedelic experience.
Finally, there is some evidence pointing towards a greater antidepressant effect associated with the dissociative or psychedelic effects of ketamine, with ‘mystical’ or spiritual experiences and experiences that generate less anxiety in session correlated with improvement. It is important to continue investigating this relationship, since many times these dissociative effects have been called side effects, thus being valued as unwanted effects.
However, S-ketamine is the most prevalent in the healthcare market with its trade name Spravato. This drug was developed with Janssen and is currently only available in hospital settings in Spain. The reason for the use of (S)-ketamine (esketamine) is the difference in the funding of studies completed up to phase III of the two compounds, being a compound from a private entity, the funding and research process has been much more dynamic and simpler than for racemic ketamine.
Although it is important to mention that ketamine and esketamine research is constantly evolving, with ongoing studies exploring new applications and refining existing protocols. There remains a substantial need for funding to address the limitations encountered in reusing and reconsidering drugs and advancing promising treatments at all stages.
For this reason, our clinic, which has almost two years of experience in Ketamine Assisted Therapy, has a team of professionals who not only know well the effects, benefits and particularities but also take care to keep up to date with the most recent research and have the necessary experience for this type of therapy. Our commitment is to keep up to date and provide our patients with the best possible care, taking advantage of advances in research and clinical practice to improve the mental health of those who rely on our treatments.
BIBLIOGRAFY
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Zanos, P., Moaddel, R., Morris, P. J., Riggs, L. M., Highland, J. N., Georgiou, P., et al. (2018).
Zhang, K., & Hashimoto, K. (2019). An update on ketamine and its two enantiomers as rapid-acting antidepressants. Expert review of neurotherapeutics, 19(1), 83-92.
