Ketamine was synthesized in 1962 by Calvin Stevens, at the Parke Davis pharmaceutical labs. It is an analogue of the compound phencyclidine (or PCP). They sought to create a drug with anesthetic properties similar to PCP, but with a shorter effect time. Ketamine was found to have a strong anesthetic effect, in addition to producing an altered state of consciousness with feelings of incorporeality and altered perceptions of the environment. It was dubbed a dissociative anesthetic, in part to avoid the negative connotations of the term ‘psychedelic’ that already existed at the time. It was approved for use by the FDA in 1970, and was used extensively during the Vietnam War because of its rapid onset time, its ability to maintain elevated blood pressure in trauma, and its minimal effects on respiration – for the latter, to this day it is still widely used in situations in which airway management is difficult.
Ketamine is composed of two isomers, S(+) and R(-) ketamine. They are similar, but have some important differences in mechanisms of action. Both are NMDA receptor antagonists, but S-ketamine blocks these receptors to a greater extent. This isomer is used more as an anesthetic, while R-ketamine seems to show better results in the treatment of depression, with fewer side effects. It has a half-life of between 2 and 4 hours in humans. In the years following its creation, ketamine was used in various studies and clinical cases dealing with patients with depression, obsessive-compulsive disorder, and addiction, among others. Fast-acting positive effects were found, indicating its possible use in the field of mental health. In 2000, the results of the first randomized controlled study by Berman and colleagues were published, providing evidence for the use of this drug for major depression.
Ketamine is a compound with highly complex pathways of action. As an antagonist of multiple receptors in the brain, ketamine is postulated to cause positive slowing of certain functional connections, promote synaptogenesis, modulate glutamate activity, and increase neuroplasticity.
Its main effect in the treatment of depression is believed to be through its role as an NMDA receptor antagonist. An antagonist prevents the activation of a receptor. However, ketamine is a non-competitive antagonist. At low doses, such as those used in depression, it does not block all receptors – this is important, as previous animal studies seem to indicate that the antidepressant effects are not as strong at high anesthetic doses.
Blocking these receptors causes an increase in the level of extracellular glutamate. This increase is associated with the dissociative effects of ketamine. Glutamate also promotes neuronal growth, thus facilitating neuroplasticity and strengthening neuronal connections. There are two ways that ketamine could cause this increase, and both are likely to occur. On the one hand, in GABAnergic interneurons it causes a reduction in inhibitory control in pyramidal neurons, causing an increase in extracellular glutamate. On the other hand, it can directly block the glutamate receptor, preventing this neurotransmitter from being transported.
However, other drugs that also act as NMDA receptor antagonists do not have these same antidepressant effects. Therefore, it is believed that its other pathways of action, some of which are not yet well understood, also have a significant impact on its functioning. Ketamine also acts on the following receptors:
– Muscarinic receptors; sensitive to the action of acetylcholine (Ach) and closely linked to memory and learning processes.
– Opioid receptors; there are several types. Partly linked to psychotomimetic effects such as euphoria and sedation.
– Adrenergic receptors; sensitive to catecholamines, they are linked to the sympathomimetic response, such as the fight or flight reaction.
– 5HT2A receptors (serotonin receptors).
Additionally, ketamine has been found to promote the transcription of BDNF (brain derived neurotrophic factor) – a great enhancer of brain plasticity. A study published in 2014 showed a strong correlation between an increase in BDNF and a decrease in depressive symptoms. Interestingly, this increase in BDNF was not found among all those administered ketamine. This small group did not respond to treatment. The exact reasons why some respond to the drug and others don’t are still not fully understood, but the same occurs with many of the other drugs and treatments available. Unfortunately, there is always a percentage of people who do not respond appropriately. On the other hand, the increase in the number of available treatment avenues is cause for celebration, as even if one method doesn’t work, chances are another will.
Another very important result published by Yang and colleagues in 2018 showed that the agonist action of NMDA receptors causes neuronal activity in the lateral habenula, an area highly linked to the reward center (motivation, gratification, decision-making and reinforcement processes). These are processes commonly out of balance in many mental health disorders, so a reactivation of this area can drive important changes in the patient.
Currently, much research continues to be published on ketamine’s mechanisms of action. More theories about its functioning are popping up – for example, through its effects on the circadian rhythms and sleep, since a large impact on sleeping rhythms and patterns has been seen in several studies. Even so, there are still important gaps in our knowledge, especially considering that many studies have been carried out in animals, and therefore the results cannot be adequately generalized to the human population.
