Right now, ketamine and its cousin esketamine are among the most-discussed drugs in the field of psychology, particularly for depression treatment.
Many people with clinical depression cannot find relief through traditional anti-depression medications like SSRIs. It's estimated that around 30% of people with depression have a treatment-resistant depression (TRD), and they need new options in medication. Both ketamine and esketamine (aka "Spravato") have strong potential to fill that role.
However, this has led some to mistakenly think that ketamine and esketamine are the same thing, or that taking ketamine at home can substitute for psychological help. This isn't true. So in this article, we'll be looking at esketamine vs ketamine: their similarities and differences, in terms of effects and current legal status.
The Basics of Ketamine
Ketamine was first formulated in the 1960s, and developed specifically as an anesthetic for surgeries. In high enough doses, it creates near-total dissociation with the body while restricting memory-formation, greatly reducing the discomfort of surgery. It also had fewer side effects than most other anesthetics used at the time, such as depressing breathing and heart rate less than alternatives.
Ketamine was used extensively in wartime applications, especially the Vietnam War. It still has surgical use today, such as in some pediatric procedures, and is also widely used by veterinarians for animal surgery.
Ketamine is an NMDA receptor antagonist. This means ketamine blocks a function in the brain which is responsible for maintaining consciousness, as well as neuroplasticity - the ability of the brain to change and store new information. This is how it works effectively as an anesthetic. Blocking NMDA receptors also has a side of effect of encouraging the brain to form new pathways between neurons. This second property has been shown to have strong anti-depressant features, as it encourages the brain to effectively 'rewire' itself, potentially around traumatic issues.
Esketamine vs Ketamine
Effects
There are two isomer variations of ketamine: R-ketamine and S-ketamine, which are basically two different ways that atoms can form the same molecule. Despite being chemically very similar, they have slightly different effects. R-ketamine tends to provide slow but long-lasting anti-depressant effects, while S-ketamine provides a faster response. In addition, S-ketamine tends to provide more dissociative effects, which can be beneficial in therapy.
Regular ketamine, such as used in surgeries or as a street drug, is a mixture of the R- and S- variations. This was to combine the features of the two isomers, in its main role as an anesthetic. On the other hand, esketamine, as the name suggests, is simply S-ketamine.
Both have been investigated for their anti-depressive properties, and have shown positive results. There's currently no clear scientific consensus on ketamine vs esketamine for which is better in treating depression.
Taking enough of either will send someone on a hallucinatory trip, which is the point of recreational ketamine use. However, the doses used in psychology are never enough to send someone into a "k-hole." Those doses are smaller, and intended to open up a person's mind without totally incapacitating them.
Clinical Use
In 2019, the FDA officially approved a version of esketamine called Spravato for treatment-resistant depression, which is delivered nasally. This is the first time a ketamine variation was officially recognized as a working anti-depressant.
While no version of ketamine or R-ketamine has yet been approved for prescription use, the FDA has been approving studies into the matter.
Spravato is delivered nasally, because that is currently seen as the best balance in terms of how quickly it works vs how quickly the body breaks it down. That said, ongoing research has suggested that an IV delivery of regular ketamine may be as effective as nasal Spravato. In general, it seems likely that ketamine will be recognized as a treatment on its own, although that's not guaranteed.
People sometimes wonder if ketamine or esketamine is covered by insurance. Basically, esketamine can be covered by insurance, as it is a recognized prescription drug. However, any use or testing of regular ketamine is currently not covered by insurance.
Legality
In the US, ketamine - in all forms - is a Schedule-II controlled substance. It is illegal to own and use privately, under any circumstance. The same is true in most other countries. Ketamine also has high potential for addiction if misused.
Ketamine and esketamine can ONLY be legally prescribed and used under the supervision of an approved doctor. Any other use risks legal action. That said, an increasing number of psychiatrists have begun using ketamine "off label" for depression treatment. The government seems to be largely tolerant of this practice as long as the practitioners are properly licensed.
How Ketamine and Esketamine are Used in Therapy
With esketamine / Spravato, it's currently taken alongside a more traditional anti-depressant. Basically, the concept is that esketamine triggers a fast-acting response that makes the patient more receptive to therapy, while the secondary anti-depressant provides longer-term support.
The user is typically given Spravato to take in a supportive setting, overseen by a psychiatrist. Once the drug kicks in, the user is typically better able to distance themselves from the psychological sources of their depression. The tendency of ketamine to help the brain rewire itself figures into this process as well.
Ketamine is currently more experimental, with some studies suggesting that ketamine by itself could be as effective as Spravato along with an SSRI. This 2022 Journal of Affective Disorders review concluded that IV ketamine is more effective than esketamine.
So why does only esketamine have FDA approval? Many believe it simply boils down to money: Ketamine is old enough to be a generic drug, and is cheap to produce by almost any chemical company. Spravato, on the other hand, is a unique drug with patent protections and can therefore be sold for much higher prices.
Esketamine vs Ketamine and You
So, would either ketamine or esketamine be viable options for helping with depression or similar psychological issues? Almost certainly. The antidepressive effects of ketamine are well documented. At this point, the main question is which version of ketamine is best for the job.
If you have treatment-resistant depression, definitely bring up the topic with your doctor or psychiatrist.
